Advertisement

MicroRNA and Posttranscriptional Dysregulation in Psychiatry

  • Michael Geaghan
    Affiliations
    School of Biomedical Sciences, Faculty of Health and Medicine, University of Newcastle, Callaghan, Australia.

    Centre for Translational Neuroscience and Mental Health, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
    Search for articles by this author
  • Murray J. Cairns
    Correspondence
    Address correspondence to Murray J. Cairns, Ph.D., School of Biomedical Sciences and Pharmacy, The University of Newcastle, Australia, University Drive, Callaghan, NSW 2308, Australia.
    Affiliations
    School of Biomedical Sciences, Faculty of Health and Medicine, University of Newcastle, Callaghan, Australia.

    Schizophrenia Research Institute, Sydney, Australia.

    Centre for Translational Neuroscience and Mental Health, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
    Search for articles by this author
Open AccessPublished:December 18, 2014DOI:https://doi.org/10.1016/j.biopsych.2014.12.009

      Abstract

      Psychiatric syndromes, including schizophrenia, mood disorders, and autism spectrum disorders, are characterized by a complex range of symptoms, including psychosis, depression, mania, and cognitive deficits. Although the mechanisms driving pathophysiology are complex and remain largely unknown, advances in the understanding of gene association and gene networks are providing significant clues to their etiology. In recent years, small noncoding RNA molecules known as microRNA (miRNA) have emerged as potential players in the pathophysiology of mental illness. These small RNAs regulate hundreds of target transcripts by modifying their stability and translation on a broad scale, influencing entire gene networks in the process. There is evidence to suggest that numerous miRNAs are dysregulated in postmortem neuropathology of neuropsychiatric disorders, and there is strong genetic support for association of miRNA genes and their targets with these conditions. This review presents the accumulated evidence linking miRNA dysregulation and dysfunction with schizophrenia, bipolar disorder, major depressive disorder, and autism spectrum disorders and the potential of miRNAs as biomarkers or therapeutics for these disorders. We further assess the functional roles of some outstanding miRNAs associated with these conditions and how they may be influencing the development of psychiatric symptoms.

      Keywords

      MicroRNAs (miRNAs) have emerged as prospective players in the pathophysiology of psychiatric disease. These small noncoding RNA molecules have the capacity to regulate the expression of many genes simultaneously and influence cellular functions at the pathway level. This capacity makes miRNAs potentially very significant in the context of complex neurodevelopmental syndromes, such as schizophrenia (SZ) and other neuropsychiatric disorders.
      The miRNA genes are dispersed throughout the genome, often set apart from protein-coding genes, although many are intronic (
      • Du T.
      • Zamore P.D.
      microPrimer: The biogenesis and function of microRNA.
      ,
      • Bartel D.P.
      MicroRNAs: Genomics, biogenesis, mechanism, and function.
      ,
      • Rodriguez A.
      • Griffiths-Jones S.
      • Ashurst J.L.
      • Bradley A.
      Identification of mammalian microRNA host genes and transcription units.
      ). After transcription, the hairpin in the primary miRNA transcript is recognized and cleaved into an ~70-nt precursor miRNA by the microprocessor complex consisting of Drosha (an RNase III) and DGCR8 ((DiGeorge syndrome critical region 8) (Figure 1) (
      • Lee Y.
      • Ahn C.
      • Han J.
      • Choi H.
      • Kim J.
      • Yim J.
      • et al.
      The nuclear RNase III Drosha initiates microRNA processing.
      ,
      • Gregory R.I.
      • Yan K.P.
      • Amuthan G.
      • Chendrimada T.
      • Doratotaj B.
      • Cooch N.
      • et al.
      The Microprocessor complex mediates the genesis of microRNAs.
      ). These are translocated to the cytoplasm where Dicer (another RNase III) removes the hairpin loop, leaving an ~22-nt double-stranded RNA. One strand of the mature miRNA is loaded into the RNA-induced silencing complex, containing Dicer, TAR RNA binding protein, and a member of the Argonaute family (
      • Gregory R.I.
      • Chendrimada T.P.
      • Cooch N.
      • Shiekhattar R.
      Human RISC couples microRNA biogenesis and posttranscriptional gene silencing.
      ). In many cases, either strand can become the functional mature miRNA, with the suffix “-3p” or “-5p” added to the name to distinguish between the strands derived from the precursor’s 3′ and 5′ ends, respectively (
      • Kozomara A.
      • Griffiths-Jones S.
      miRBase: integrating microRNA annotation and deep-sequencing data.
      ). The miRNA–RNA-induced silencing complex binds to the 3′ untranslated region of a messenger RNA target through complementarity to nucleotides 2–8—the “seed region”—of the miRNA (
      • Lewis B.P.
      • Shih I.H.
      • Jones-Rhoades M.W.
      • Bartel D.P.
      • Burge C.B.
      Prediction of mammalian microRNA targets.
      ) and destabilizes the transcript, or represses its translation, often followed by degradation, making it possible to assess miRNA function via gene expression profiling (
      • Carroll A.P.
      • Tran N.
      • Tooney P.A.
      • Cairns M.J.
      Alternative mRNA fates identified in microRNA-associated transcriptome analysis.
      ,
      • Lim L.P.
      • Lau N.C.
      • Garrett-Engele P.
      • Grimson A.
      • Schelter J.M.
      • Castle J.
      • et al.
      Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs.
      ).
      Figure thumbnail gr1
      Figure 1MicroRNA (miRNA) structure, biogenesis, and function. RNA polymerase II transcribes the primary miRNA transcript, which is processed in the nucleus by Drosha and the microprocessor complex into the ~70-nt precursor miRNA hairpin. This hairpin is exported to the cytoplasm by Exportin-5 and Ran-GTP, where Dicer cuts off the loop end of the hairpin, leaving an ~22-nt long, imperfectly base-paired RNA duplex. One of these strands is the mature miRNA, which is loaded into the RNA-induced silencing complex, which then mediates the silencing of messenger RNA molecules, which are targeted based on complementarity to the loaded miRNA. The RNA-induced silencing complex silences gene expression by inhibiting translation through interference 5′ cap-binding protein interactions or degrading the target messenger RNA by compromising its stability through poly(A) tail deadenylation, 5′ cap loss, and exoribonuclease degradation. DGCR8, DiGeorge syndrome critical region 8; mRNA, messenger RNA; pre-miRNA, precursor microRNA; pri-miRNA, primary microRNA transcript; RISC, RNA-induced silencing complex.
      The importance of miRNAs and their biogenesis to the developing brain has been known for almost a decade, with a study demonstrating that zebrafish depleted of functional DICER protein display severe developmental abnormalities, particularly in the brain (
      • Giraldez A.J.
      • Cinalli R.M.
      • Glasner M.E.
      • Enright A.J.
      • Thomson J.M.
      • Baskerville S.
      • et al.
      MicroRNAs regulate brain morphogenesis in zebrafish.
      ). These mutants developed asymmetrically, with severely reduced ventricle size and no midbrain-hindbrain boundary. Similarly, mice with selective Dicer deletion in excitatory forebrain neurons displayed enlarged lateral ventricles associated with increased postnatal cell death, decreased dendritic branching, abnormally long dendritic spines, and loss of axonal pathfinding (
      • Davis T.H.
      • Cuellar T.L.
      • Koch S.M.
      • Barker A.J.
      • Harfe B.D.
      • McManus M.T.
      • et al.
      Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus.
      ). Additionally, these relatively short-lived mutants were microcephalic and displayed ataxia. When Dicer is lost from dopamine D1 receptor neurons in the striatum, mice have a decreased life span, smaller brain size and mass, and smaller medium spiny neurons and show ataxia and astrogliosis (
      • Cuellar T.L.
      • Davis T.H.
      • Nelson P.T.
      • Loeb G.B.
      • Harfe B.D.
      • Ullian E.
      • et al.
      Dicer loss in striatal neurons produces behavioral and neuroanatomical phenotypes in the absence of neurodegeneration.
      ). These studies demonstrate that miRNA biogenesis is extremely important for normal brain development and function.
      In this review, we revisit some of the recent highlights in the neurobiology of miRNA associated with neuropsychiatric syndromes and examine the support for their involvement in psychiatric pathophysiology. We also discuss the possible clinical applications for miRNAs in psychiatric treatment and what is needed for the field to progress.

      Evidence for miRNA Dysfunction in Psychiatric Disorders

      In view of the vital role for miRNAs in the brain, it is not surprising that they are also emerging as significant players in the pathophysiology of several neurologic conditions. There is substantial research supporting the dysregulation of miRNA in psychiatric syndromes from expression studies that use microarrays and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) analyses and genetic association studies that identify single nucleotide polymorphisms (SNPs) and copy number variations (CNVs). Expression studies have typically used either postmortem brain or other tissue samples such as peripheral blood mononuclear cells. Although postmortem brain samples provide direct evidence of miRNA dysregulation within the brain, peripheral tissue samples can be obtained from living subjects and have the potential to yield biomarkers that could be used as diagnostic tools. Genetics studies do not assess miRNA expression levels, but they present evidence for a causative role for miRNAs in psychiatric illness; in contrast, expression studies can demonstrate only a correlation between miRNAs and disease. We review the evidence linking SZ, bipolar disorder (BD), major depressive disorder (MDD), and autism spectrum disorders (ASDs) with altered miRNA expression and genetic variations that interfere with miRNA function.

      SZ

      The association between miRNA dysfunction and SZ has been reported in several studies (Table S1 in Supplement 1). One of the earliest expression studies investigated postmortem brain tissue from the dorsolateral prefrontal cortex (DLPFC) Brodmann area (BA) 9 (
      • Perkins D.O.
      • Jeffries C.D.
      • Jarskog L.F.
      • Thomson J.M.
      • Woods K.
      • Newman M.A.
      • et al.
      microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder.
      ). Using a custom microarray, the authors identified 16 significantly differentially expressed miRNAs in subjects with SZ compared with control subjects including miR-26b, miR-30a-5p, miR-30b/d/e, miR-29a/b/c, miR-195, miR-92, miR-20b, miR-212, miR-7, miR-24, miR-9-3p, and miR-106b. Only miR-106b was upregulated leaving the remaining 15 miRNAs downregulated, 7 of which were also confirmed by qRT-PCR in a small subcohort. Using a similar approach, we investigated postmortem miRNA levels in the DLPFC (BA9) and the superior temporal gyrus (BA22) (
      • Beveridge N.J.
      • Gardiner E.
      • Carroll A.P.
      • Tooney P.A.
      • Cairns M.J.
      Schizophrenia is associated with an increase in cortical microRNA biogenesis.
      ,
      • Beveridge N.J.
      • Tooney P.A.
      • Carroll A.P.
      • Gardiner E.
      • Bowden N.
      • Scott R.J.
      • et al.
      Dysregulation of miRNA 181b in the temporal cortex in schizophrenia.
      ). Among numerous miRNA species showing elevated expression was miR-107 and members of the miR-15 family (miR-15a/b, miR-16, and miR-195), which all share similar seed regions and common target genes and roles in neuronal function, including neuronal proliferation and differentiation, making them important with regard to the neurodevelopmental aspect of SZ (Supplement 1) (
      • Liu C.
      • Teng Z.Q.
      • McQuate A.L.
      • Jobe E.M.
      • Christ C.C.
      • von Hoyningen-Huene S.J.
      • et al.
      An epigenetic feedback regulatory loop involving microRNA-195 and MBD1 governs neural stem cell differentiation.
      ,
      • Moncini S.
      • Salvi A.
      • Zuccotti P.
      • Viero G.
      • Quattrone A.
      • Barlati S.
      • et al.
      The role of miR-103 and miR-107 in regulation of CDK5R1 expression and in cellular migration.
      ). Members of this family have been identified in other psychiatric disorders (Table 1). Additionally, the miRNA biogenesis gene DGCR8 was found to be upregulated, suggesting that miRNA biogenesis was increased and responsible for the global elevation of miRNA. This finding was significant given that DGCR8 is also affected by the hemizygous deletion of 22q11.2 deletion syndrome, which predisposes individuals to DiGeorge syndrome and a high risk of developing SZ (
      • Bassett A.S.
      • Chow E.W.
      • Husted J.
      • Weksberg R.
      • Caluseriu O.
      • Webb G.D.
      • et al.
      Clinical features of 78 adults with 22q11 deletion syndrome.
      ,
      • Shiohama A.
      • Sasaki T.
      • Noda S.
      • Minoshima S.
      • Shimizu N.
      Molecular cloning and expression analysis of a novel gene DGCR8 located in the DiGeorge syndrome chromosomal region.
      ). We also observed an upregulation of miRNAs in SZ, including miR-107 again, alongside an upregulation of the miRNA biogenesis gene Dicer in the DLPFC (BA46) (
      • Santarelli D.M.
      • Beveridge N.J.
      • Tooney P.A.
      • Cairns M.J.
      Upregulation of dicer and microRNA expression in the dorsolateral prefrontal cortex Brodmann area 46 in schizophrenia.
      ).
      Table 1Psychiatric Disease–Associated miRNAs Identified by Multiple Studies
      miRNAAuthorsmiRNAAuthors
      SchizophreniaMajor Depressive Disorder
      miR-106b
      MiRNA has been identified multiple times in more than one of these conditions.
      Perkins et al., 2007 (
      • Perkins D.O.
      • Jeffries C.D.
      • Jarskog L.F.
      • Thomson J.M.
      • Woods K.
      • Newman M.A.
      • et al.
      microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder.
      ); Moreau et al., 2011 (
      • Moreau M.P.
      • Bruse S.E.
      • David-Rus R.
      • Buyske S.
      • Brzustowicz L.M.
      Altered microRNA expression profiles in postmortem brain samples from individuals with schizophrenia and bipolar disorder.
      ); Smalheiser et al., 2014 (
      • Smalheiser N.R.
      • Lugli G.
      • Zhang H.
      • Rizavi H.
      • Cook E.H.
      • Dwivedi Y.
      Expression of microRNAs and other small RNAs in prefrontal cortex in schizophrenia, bipolar disorder and depressed subjects.
      )
      miR-107
      MiRNA has been identified multiple times in more than one of these conditions.
      Smalheiser et al., 2011 (
      • Smalheiser N.R.
      • Lugli G.
      • Rizavi H.S.
      • Zhang H.
      • Torvik V.I.
      • Pandey G.N.
      • et al.
      MicroRNA expression in rat brain exposed to repeated inescapable shock: Differential alterations in learned helplessness vs. non-learned helplessness.
      ); Belzeaux et al., 2012 (
      • Belzeaux R.
      • Bergon A.
      • Jeanjean V.
      • Loriod B.
      • Formisano-Treziny C.
      • Verrier L.
      • et al.
      Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode.
      )
      miR-107
      MiRNA has been identified multiple times in more than one of these conditions.
      Beveridge et al., 2010 (
      • Beveridge N.J.
      • Gardiner E.
      • Carroll A.P.
      • Tooney P.A.
      • Cairns M.J.
      Schizophrenia is associated with an increase in cortical microRNA biogenesis.
      ); Santarelli et al., 2011 (
      • Santarelli D.M.
      • Beveridge N.J.
      • Tooney P.A.
      • Cairns M.J.
      Upregulation of dicer and microRNA expression in the dorsolateral prefrontal cortex Brodmann area 46 in schizophrenia.
      )
      miR-125aSmalheiser et al., 2011 (
      • Smalheiser N.R.
      • Lugli G.
      • Rizavi H.S.
      • Zhang H.
      • Torvik V.I.
      • Pandey G.N.
      • et al.
      MicroRNA expression in rat brain exposed to repeated inescapable shock: Differential alterations in learned helplessness vs. non-learned helplessness.
      ); Cao et al., 2013 (
      • Cao M.Q.
      • Chen D.H.
      • Zhang C.H.
      • Wu Z.Z.
      Screening of specific microRNA in hippocampus of depression model rats and intervention effect of Chaihu Shugan San [in Chinese].
      )
      miR-132
      MiRNA has been identified multiple times in more than one of these conditions.
      Kim et al., 2010 (
      • Kim A.H.
      • Reimers M.
      • Maher B.
      • Williamson V.
      • McMichael O.
      • McClay J.L.
      • et al.
      MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders.
      ); Miller et al., 2012 (
      • Miller B.H.
      • Zeier Z.
      • Xi L.
      • Lanz T.A.
      • Deng S.
      • Strathmann J.
      • et al.
      MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function.
      )
      miR-132
      MiRNA has been identified multiple times in more than one of these conditions.
      Smalheiser et al., 2011 (
      • Smalheiser N.R.
      • Lugli G.
      • Rizavi H.S.
      • Zhang H.
      • Torvik V.I.
      • Pandey G.N.
      • et al.
      MicroRNA expression in rat brain exposed to repeated inescapable shock: Differential alterations in learned helplessness vs. non-learned helplessness.
      ); Li et al., 2013 (
      • Li Y.J.
      • Xu M.
      • Gao Z.H.
      • Wang Y.Q.
      • Yue Z.
      • Zhang Y.X.
      • et al.
      Alterations of serum levels of BDNF-related miRNAs in patients with depression.
      )
      miR-132*Kim et al., 2010 (
      • Kim A.H.
      • Reimers M.
      • Maher B.
      • Williamson V.
      • McMichael O.
      • McClay J.L.
      • et al.
      MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders.
      ); Miller et al., 2012 (
      • Miller B.H.
      • Zeier Z.
      • Xi L.
      • Lanz T.A.
      • Deng S.
      • Strathmann J.
      • et al.
      MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function.
      )
      miR-142-3pSmalheiser et al., 2011 (
      • Smalheiser N.R.
      • Lugli G.
      • Rizavi H.S.
      • Zhang H.
      • Torvik V.I.
      • Pandey G.N.
      • et al.
      MicroRNA expression in rat brain exposed to repeated inescapable shock: Differential alterations in learned helplessness vs. non-learned helplessness.
      ); Smalheiser et al., 2012 (
      • Smalheiser N.R.
      • Lugli G.
      • Rizavi H.S.
      • Torvik V.I.
      • Turecki G.
      • Dwivedi Y.
      MicroRNA expression is down-regulated and reorganized in prefrontal cortex of depressed suicide subjects.
      )
      miR-134Santarelli et al., 2011 (
      • Santarelli D.M.
      • Beveridge N.J.
      • Tooney P.A.
      • Cairns M.J.
      Upregulation of dicer and microRNA expression in the dorsolateral prefrontal cortex Brodmann area 46 in schizophrenia.
      ); Gardiner et al., 2012 (
      • Gardiner E.
      • Beveridge N.J.
      • Wu J.Q.
      • Carr V.
      • Scott R.J.
      • Tooney P.A.
      • et al.
      Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells.
      )
      miR-145
      MiRNA has been identified multiple times in more than one of these conditions.
      Smalheiser et al., 2011 (
      • Smalheiser N.R.
      • Lugli G.
      • Rizavi H.S.
      • Zhang H.
      • Torvik V.I.
      • Pandey G.N.
      • et al.
      MicroRNA expression in rat brain exposed to repeated inescapable shock: Differential alterations in learned helplessness vs. non-learned helplessness.
      ); Belzeaux et al., 2012 (
      • Belzeaux R.
      • Bergon A.
      • Jeanjean V.
      • Loriod B.
      • Formisano-Treziny C.
      • Verrier L.
      • et al.
      Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode.
      )
      miR-137Ripke et al., 2011 (
      • Ripke S.
      • Sanders A.
      • Kendler K.
      • Levinson D.
      • Sklar P.
      • Holmans P.
      • et al.
      Genome-wide association study identifies five new schizophrenia loci.
      ); Whalley et al., 2012 (
      • Whalley H.C.
      • Papmeyer M.
      • Romaniuk L.
      • Sprooten E.
      • Johnstone E.C.
      • Hall J.
      • et al.
      Impact of a microRNA MIR137 susceptibility variant on brain function in people at high genetic risk of schizophrenia or bipolar disorder.
      ); Green et al., 2013 (
      • Green M.J.
      • Cairns M.J.
      • Wu J.
      • Dragovic M.
      • Jablensky A.
      • Tooney P.A.
      • et al.
      Genome-wide supported variant MIR137 and severe negative symptoms predict membership of an impaired cognitive subtype of schizophrenia.
      )
      miR-182Smalheiser et al., 2011 (
      • Smalheiser N.R.
      • Lugli G.
      • Rizavi H.S.
      • Zhang H.
      • Torvik V.I.
      • Pandey G.N.
      • et al.
      MicroRNA expression in rat brain exposed to repeated inescapable shock: Differential alterations in learned helplessness vs. non-learned helplessness.
      ); Li et al., 2013 (
      • Li Y.J.
      • Xu M.
      • Gao Z.H.
      • Wang Y.Q.
      • Yue Z.
      • Zhang Y.X.
      • et al.
      Alterations of serum levels of BDNF-related miRNAs in patients with depression.
      ); Cao et al., 2013 (
      • Cao M.Q.
      • Chen D.H.
      • Zhang C.H.
      • Wu Z.Z.
      Screening of specific microRNA in hippocampus of depression model rats and intervention effect of Chaihu Shugan San [in Chinese].
      )
      miR-150Santarelli et al., 2011 (
      • Santarelli D.M.
      • Beveridge N.J.
      • Tooney P.A.
      • Cairns M.J.
      Upregulation of dicer and microRNA expression in the dorsolateral prefrontal cortex Brodmann area 46 in schizophrenia.
      ); Miller et al., 2012 (
      • Miller B.H.
      • Zeier Z.
      • Xi L.
      • Lanz T.A.
      • Deng S.
      • Strathmann J.
      • et al.
      MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function.
      )
      miR-200cSmalheiser et al., 2011 (
      • Smalheiser N.R.
      • Lugli G.
      • Rizavi H.S.
      • Zhang H.
      • Torvik V.I.
      • Pandey G.N.
      • et al.
      MicroRNA expression in rat brain exposed to repeated inescapable shock: Differential alterations in learned helplessness vs. non-learned helplessness.
      ); Belzeaux et al., 2012 (
      • Belzeaux R.
      • Bergon A.
      • Jeanjean V.
      • Loriod B.
      • Formisano-Treziny C.
      • Verrier L.
      • et al.
      Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode.
      )
      miR-15aaBeveridge et al., 2010 (
      • Beveridge N.J.
      • Gardiner E.
      • Carroll A.P.
      • Tooney P.A.
      • Cairns M.J.
      Schizophrenia is associated with an increase in cortical microRNA biogenesis.
      ); Moreau et al., 2011 (
      • Moreau M.P.
      • Bruse S.E.
      • David-Rus R.
      • Buyske S.
      • Brzustowicz L.M.
      Altered microRNA expression profiles in postmortem brain samples from individuals with schizophrenia and bipolar disorder.
      )
      miR-298Smalheiser et al., 2011 (
      • Smalheiser N.R.
      • Lugli G.
      • Rizavi H.S.
      • Zhang H.
      • Torvik V.I.
      • Pandey G.N.
      • et al.
      MicroRNA expression in rat brain exposed to repeated inescapable shock: Differential alterations in learned helplessness vs. non-learned helplessness.
      ); Cao et al., 2013 (
      • Cao M.Q.
      • Chen D.H.
      • Zhang C.H.
      • Wu Z.Z.
      Screening of specific microRNA in hippocampus of depression model rats and intervention effect of Chaihu Shugan San [in Chinese].
      )
      miR-16Beveridge et al., 2010 (
      • Beveridge N.J.
      • Gardiner E.
      • Carroll A.P.
      • Tooney P.A.
      • Cairns M.J.
      Schizophrenia is associated with an increase in cortical microRNA biogenesis.
      ); Smalheiser et al., 2014 (
      • Smalheiser N.R.
      • Lugli G.
      • Zhang H.
      • Rizavi H.
      • Cook E.H.
      • Dwivedi Y.
      Expression of microRNAs and other small RNAs in prefrontal cortex in schizophrenia, bipolar disorder and depressed subjects.
      )
      miR-376a*Smalheiser et al., 2011 (
      • Smalheiser N.R.
      • Lugli G.
      • Rizavi H.S.
      • Zhang H.
      • Torvik V.I.
      • Pandey G.N.
      • et al.
      MicroRNA expression in rat brain exposed to repeated inescapable shock: Differential alterations in learned helplessness vs. non-learned helplessness.
      ); Smalheiser et al., 2012 (
      • Smalheiser N.R.
      • Lugli G.
      • Rizavi H.S.
      • Torvik V.I.
      • Turecki G.
      • Dwivedi Y.
      MicroRNA expression is down-regulated and reorganized in prefrontal cortex of depressed suicide subjects.
      ); Belzeaux et al., 2012 (
      • Belzeaux R.
      • Bergon A.
      • Jeanjean V.
      • Loriod B.
      • Formisano-Treziny C.
      • Verrier L.
      • et al.
      Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode.
      )
      miR-17
      MiRNA has been identified multiple times in more than one of these conditions.
      Santarelli et al., 2011 (
      • Santarelli D.M.
      • Beveridge N.J.
      • Tooney P.A.
      • Cairns M.J.
      Upregulation of dicer and microRNA expression in the dorsolateral prefrontal cortex Brodmann area 46 in schizophrenia.
      ); Wong et al., 2013 (
      • Wong J.
      • Duncan C.E.
      • Beveridge N.J.
      • Webster M.J.
      • Cairns M.J.
      • Weickert C.S.
      Expression of NPAS3 in the human cortex and evidence of its posttranscriptional regulation by miR-17 during development, with implications for schizophrenia.
      ); Smalheiser et al., 2014 (
      • Smalheiser N.R.
      • Lugli G.
      • Zhang H.
      • Rizavi H.
      • Cook E.H.
      • Dwivedi Y.
      Expression of microRNAs and other small RNAs in prefrontal cortex in schizophrenia, bipolar disorder and depressed subjects.
      )
      miR-381Smalheiser et al., 2011 (
      • Smalheiser N.R.
      • Lugli G.
      • Rizavi H.S.
      • Zhang H.
      • Torvik V.I.
      • Pandey G.N.
      • et al.
      MicroRNA expression in rat brain exposed to repeated inescapable shock: Differential alterations in learned helplessness vs. non-learned helplessness.
      ); Belzeaux et al., 2012 (
      • Belzeaux R.
      • Bergon A.
      • Jeanjean V.
      • Loriod B.
      • Formisano-Treziny C.
      • Verrier L.
      • et al.
      Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode.
      )
      miR-181bBeveridge et al., 2008 (
      • Beveridge N.J.
      • Tooney P.A.
      • Carroll A.P.
      • Gardiner E.
      • Bowden N.
      • Scott R.J.
      • et al.
      Dysregulation of miRNA 181b in the temporal cortex in schizophrenia.
      ); Beveridge et al., 2010 (
      • Beveridge N.J.
      • Gardiner E.
      • Carroll A.P.
      • Tooney P.A.
      • Cairns M.J.
      Schizophrenia is associated with an increase in cortical microRNA biogenesis.
      ); Shi et al., 2012 (
      • Shi W.
      • Du J.
      • Qi Y.
      • Liang G.
      • Wang T.
      • Li S.
      • et al.
      Aberrant expression of serum miRNAs in schizophrenia.
      )
      miR-494Smalheiser et al., 2012 (
      • Smalheiser N.R.
      • Lugli G.
      • Rizavi H.S.
      • Torvik V.I.
      • Turecki G.
      • Dwivedi Y.
      MicroRNA expression is down-regulated and reorganized in prefrontal cortex of depressed suicide subjects.
      ); Belzeaux et al., 2012 (
      • Belzeaux R.
      • Bergon A.
      • Jeanjean V.
      • Loriod B.
      • Formisano-Treziny C.
      • Verrier L.
      • et al.
      Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode.
      )
      miR-195
      MiRNA has been identified multiple times in more than one of these conditions.
      Perkins et al., 2007 (
      • Perkins D.O.
      • Jeffries C.D.
      • Jarskog L.F.
      • Thomson J.M.
      • Woods K.
      • Newman M.A.
      • et al.
      microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder.
      ); Beveridge et al., 2010 (
      • Beveridge N.J.
      • Gardiner E.
      • Carroll A.P.
      • Tooney P.A.
      • Cairns M.J.
      Schizophrenia is associated with an increase in cortical microRNA biogenesis.
      ); Shi et al., 2012 (
      • Shi W.
      • Du J.
      • Qi Y.
      • Liang G.
      • Wang T.
      • Li S.
      • et al.
      Aberrant expression of serum miRNAs in schizophrenia.
      )
      miR-497Smalheiser et al., 2011 (
      • Smalheiser N.R.
      • Lugli G.
      • Rizavi H.S.
      • Zhang H.
      • Torvik V.I.
      • Pandey G.N.
      • et al.
      MicroRNA expression in rat brain exposed to repeated inescapable shock: Differential alterations in learned helplessness vs. non-learned helplessness.
      ); Smalheiser et al., 2012 (
      • Smalheiser N.R.
      • Lugli G.
      • Rizavi H.S.
      • Torvik V.I.
      • Turecki G.
      • Dwivedi Y.
      MicroRNA expression is down-regulated and reorganized in prefrontal cortex of depressed suicide subjects.
      )
      miR-212Perkins et al., 2007 (
      • Perkins D.O.
      • Jeffries C.D.
      • Jarskog L.F.
      • Thomson J.M.
      • Woods K.
      • Newman M.A.
      • et al.
      microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder.
      ); Kim et al., 2010 (
      • Kim A.H.
      • Reimers M.
      • Maher B.
      • Williamson V.
      • McMichael O.
      • McClay J.L.
      • et al.
      MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders.
      )
      Autism Spectrum Disorders
      miR-219-3pShi et al., 2012 (
      • Shi W.
      • Du J.
      • Qi Y.
      • Liang G.
      • Wang T.
      • Li S.
      • et al.
      Aberrant expression of serum miRNAs in schizophrenia.
      ); Smalheiser et al., 2014 (
      • Smalheiser N.R.
      • Lugli G.
      • Zhang H.
      • Rizavi H.
      • Cook E.H.
      • Dwivedi Y.
      Expression of microRNAs and other small RNAs in prefrontal cortex in schizophrenia, bipolar disorder and depressed subjects.
      )
      miR-106b
      MiRNA has been identified multiple times in more than one of these conditions.
      Abu-Elneel et al., 2008 (
      • Abu-Elneel K.
      • Liu T.
      • Gazzaniga F.S.
      • Nishimura Y.
      • Wall D.P.
      • Geschwind D.H.
      • et al.
      Heterogeneous dysregulation of microRNAs across the autism spectrum.
      ); Sarachana et al., 2010 (
      • Sarachana T.
      • Zhou R.
      • Chen G.
      • Manji H.K.
      • Hu V.W.
      Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines.
      )
      miR-24Perkins et al., 2007 (
      • Perkins D.O.
      • Jeffries C.D.
      • Jarskog L.F.
      • Thomson J.M.
      • Woods K.
      • Newman M.A.
      • et al.
      microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder.
      ); Xu et al., 2010 (
      • Xu Y.
      • Li F.
      • Zhang B.
      • Zhang K.
      • Zhang F.
      • Huang X.
      • et al.
      MicroRNAs and target site screening reveals a pre-microRNA-30e variant associated with schizophrenia.
      )
      miR-1286Vaishnavi et al., 2013 (
      • Vaishnavi V.
      • Manikandan M.
      • Tiwary B.K.
      • Munirajan A.K.
      Insights on the functional impact of microRNAs present in autism-associated copy number variants.
      ); Marrale et al., 2014 (
      • Marrale M.
      • Albanese N.N.
      • Cali F.
      • Romano V.
      Assessing the impact of copy number variants on miRNA genes in autism by Monte Carlo simulation.
      )
      miR-26bPerkins et al., 2007 (
      • Perkins D.O.
      • Jeffries C.D.
      • Jarskog L.F.
      • Thomson J.M.
      • Woods K.
      • Newman M.A.
      • et al.
      microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder.
      ); Beveridge et al., 2010 (
      • Beveridge N.J.
      • Gardiner E.
      • Carroll A.P.
      • Tooney P.A.
      • Cairns M.J.
      Schizophrenia is associated with an increase in cortical microRNA biogenesis.
      )
      miR-1306Vaishnavi et al., 2013 (
      • Vaishnavi V.
      • Manikandan M.
      • Tiwary B.K.
      • Munirajan A.K.
      Insights on the functional impact of microRNAs present in autism-associated copy number variants.
      ); Marrale et al., 2014 (
      • Marrale M.
      • Albanese N.N.
      • Cali F.
      • Romano V.
      Assessing the impact of copy number variants on miRNA genes in autism by Monte Carlo simulation.
      )
      miR-29c
      MiRNA has been identified multiple times in more than one of these conditions.
      Perkins et al., 2007 (
      • Perkins D.O.
      • Jeffries C.D.
      • Jarskog L.F.
      • Thomson J.M.
      • Woods K.
      • Newman M.A.
      • et al.
      microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder.
      ); Beveridge et al., 2010 (
      • Beveridge N.J.
      • Gardiner E.
      • Carroll A.P.
      • Tooney P.A.
      • Cairns M.J.
      Schizophrenia is associated with an increase in cortical microRNA biogenesis.
      )
      miR-132
      MiRNA has been identified multiple times in more than one of these conditions.
      Abu-Elneel et al., 2008 (
      • Abu-Elneel K.
      • Liu T.
      • Gazzaniga F.S.
      • Nishimura Y.
      • Wall D.P.
      • Geschwind D.H.
      • et al.
      Heterogeneous dysregulation of microRNAs across the autism spectrum.
      ); Talebizadeh et al., 2008 (
      • Talebizadeh Z.
      • Butler M.G.
      • Theodoro M.F.
      Feasibility and relevance of examining lymphoblastoid cell lines to study role of microRNAs in autism.
      ); Sarachana et al., 2010 (
      • Sarachana T.
      • Zhou R.
      • Chen G.
      • Manji H.K.
      • Hu V.W.
      Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines.
      )
      miR-30bPerkins et al., 2007 (
      • Perkins D.O.
      • Jeffries C.D.
      • Jarskog L.F.
      • Thomson J.M.
      • Woods K.
      • Newman M.A.
      • et al.
      microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder.
      ); Mellios et al., 2012 (
      • Mellios N.
      • Galdzicka M.
      • Ginns E.
      • Baker S.P.
      • Rogaev E.
      • Xu J.
      • et al.
      Gender-specific reduction of estrogen-sensitive small RNA, miR-30b, in subjects with schizophrenia.
      )
      miR-146bAbu-Elneel et al., 2008 (
      • Abu-Elneel K.
      • Liu T.
      • Gazzaniga F.S.
      • Nishimura Y.
      • Wall D.P.
      • Geschwind D.H.
      • et al.
      Heterogeneous dysregulation of microRNAs across the autism spectrum.
      ); Talebizadeh et al., 2008 (
      • Talebizadeh Z.
      • Butler M.G.
      • Theodoro M.F.
      Feasibility and relevance of examining lymphoblastoid cell lines to study role of microRNAs in autism.
      )
      miR-30ePerkins et al., 2007 (
      • Perkins D.O.
      • Jeffries C.D.
      • Jarskog L.F.
      • Thomson J.M.
      • Woods K.
      • Newman M.A.
      • et al.
      microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder.
      ); Xu et al., 2010 (
      • Xu Y.
      • Li F.
      • Zhang B.
      • Zhang K.
      • Zhang F.
      • Huang X.
      • et al.
      MicroRNAs and target site screening reveals a pre-microRNA-30e variant associated with schizophrenia.
      )
      miR-148b
      MiRNA has been identified multiple times in more than one of these conditions.
      Abu-Elneel et al., 2008 (
      • Abu-Elneel K.
      • Liu T.
      • Gazzaniga F.S.
      • Nishimura Y.
      • Wall D.P.
      • Geschwind D.H.
      • et al.
      Heterogeneous dysregulation of microRNAs across the autism spectrum.
      ); Sarachana et al., 2010 (
      • Sarachana T.
      • Zhou R.
      • Chen G.
      • Manji H.K.
      • Hu V.W.
      Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines.
      )
      miR-320Tabares-Seisdedos et al., 2009 (
      • Tabares-Seisdedos R.
      • Rubenstein J.L.
      Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: Implications for schizophrenia, autism and cancer.
      ); Miller et al., 2012 (
      • Miller B.H.
      • Zeier Z.
      • Xi L.
      • Lanz T.A.
      • Deng S.
      • Strathmann J.
      • et al.
      MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function.
      )
      miR-149Vaishnavi et al., 2013 (
      • Vaishnavi V.
      • Manikandan M.
      • Tiwary B.K.
      • Munirajan A.K.
      Insights on the functional impact of microRNAs present in autism-associated copy number variants.
      ); Marrale et al., 2014 (
      • Marrale M.
      • Albanese N.N.
      • Cali F.
      • Romano V.
      Assessing the impact of copy number variants on miRNA genes in autism by Monte Carlo simulation.
      )
      miR-34aKim et al., 2010 (
      • Kim A.H.
      • Reimers M.
      • Maher B.
      • Williamson V.
      • McMichael O.
      • McClay J.L.
      • et al.
      MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders.
      ); Lai et al., 2011 (
      • Lai C.Y.
      • Yu S.L.
      • Hsieh M.H.
      • Chen C.H.
      • Chen H.Y.
      • Wen C.C.
      • et al.
      MicroRNA expression aberration as potential peripheral blood biomarkers for schizophrenia.
      )
      miR-17
      MiRNA has been identified multiple times in more than one of these conditions.
      Kannu et al., 2013 (
      • Kannu P.
      • Campos-Xavier A.B.
      • Hull D.
      • Martinet D.
      • Ballhausen D.
      • Bonafe L.
      Post-axial polydactyly type A2, overgrowth and autistic traits associated with a chromosome 13q31.3 microduplication encompassing miR-17-92 and GPC5.
      ); Hemmat et al., 2014 (
      • Hemmat M.
      • Rumple M.J.
      • Mahon L.W.
      • Strom C.M.
      • Anguiano A.
      • Talai M.
      • et al.
      Short stature, digit anomalies and dysmorphic facial features are associated with the duplication of miR-17 ~ 92 cluster.
      )
      miR-432Lai et al., 2011 (
      • Lai C.Y.
      • Yu S.L.
      • Hsieh M.H.
      • Chen C.H.
      • Chen H.Y.
      • Wen C.C.
      • et al.
      MicroRNA expression aberration as potential peripheral blood biomarkers for schizophrenia.
      ); Gardiner et al., 2012 (
      • Gardiner E.
      • Beveridge N.J.
      • Wu J.Q.
      • Carr V.
      • Scott R.J.
      • Tooney P.A.
      • et al.
      Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells.
      )
      miR-185Sarachana et al., 2010 (
      • Sarachana T.
      • Zhou R.
      • Chen G.
      • Manji H.K.
      • Hu V.W.
      Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines.
      ); Vaishnavi et al., 2013 (
      • Vaishnavi V.
      • Manikandan M.
      • Tiwary B.K.
      • Munirajan A.K.
      Insights on the functional impact of microRNAs present in autism-associated copy number variants.
      ); Marrale et al., 2014 (
      • Marrale M.
      • Albanese N.N.
      • Cali F.
      • Romano V.
      Assessing the impact of copy number variants on miRNA genes in autism by Monte Carlo simulation.
      )
      miR-544Kim et al., 2010 (
      • Kim A.H.
      • Reimers M.
      • Maher B.
      • Williamson V.
      • McMichael O.
      • McClay J.L.
      • et al.
      MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders.
      ); Gardiner et al., 2012 (
      • Gardiner E.
      • Beveridge N.J.
      • Wu J.Q.
      • Carr V.
      • Scott R.J.
      • Tooney P.A.
      • et al.
      Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells.
      )
      miR-18aKannu et al., 2013 (
      • Kannu P.
      • Campos-Xavier A.B.
      • Hull D.
      • Martinet D.
      • Ballhausen D.
      • Bonafe L.
      Post-axial polydactyly type A2, overgrowth and autistic traits associated with a chromosome 13q31.3 microduplication encompassing miR-17-92 and GPC5.
      ); Hemmat et al., 2014 (
      • Hemmat M.
      • Rumple M.J.
      • Mahon L.W.
      • Strom C.M.
      • Anguiano A.
      • Talai M.
      • et al.
      Short stature, digit anomalies and dysmorphic facial features are associated with the duplication of miR-17 ~ 92 cluster.
      )
      miR-652Lai et al., 2011 (
      • Lai C.Y.
      • Yu S.L.
      • Hsieh M.H.
      • Chen C.H.
      • Chen H.Y.
      • Wen C.C.
      • et al.
      MicroRNA expression aberration as potential peripheral blood biomarkers for schizophrenia.
      ); Santarelli et al., 2011 (
      • Santarelli D.M.
      • Beveridge N.J.
      • Tooney P.A.
      • Cairns M.J.
      Upregulation of dicer and microRNA expression in the dorsolateral prefrontal cortex Brodmann area 46 in schizophrenia.
      )
      miR-195
      MiRNA has been identified multiple times in more than one of these conditions.
      Sarachana et al., 2010 (
      • Sarachana T.
      • Zhou R.
      • Chen G.
      • Manji H.K.
      • Hu V.W.
      Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines.
      ); Vaishnavi et al., 2013 (
      • Vaishnavi V.
      • Manikandan M.
      • Tiwary B.K.
      • Munirajan A.K.
      Insights on the functional impact of microRNAs present in autism-associated copy number variants.
      )
      miR-7Perkins et al., 2007 (
      • Perkins D.O.
      • Jeffries C.D.
      • Jarskog L.F.
      • Thomson J.M.
      • Woods K.
      • Newman M.A.
      • et al.
      microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder.
      ); Beveridge et al., 2010 (
      • Beveridge N.J.
      • Gardiner E.
      • Carroll A.P.
      • Tooney P.A.
      • Cairns M.J.
      Schizophrenia is associated with an increase in cortical microRNA biogenesis.
      ); Kim et al., 2010 (
      • Kim A.H.
      • Reimers M.
      • Maher B.
      • Williamson V.
      • McMichael O.
      • McClay J.L.
      • et al.
      MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders.
      )
      miR-199b-5pSarachana et al., 2010 (
      • Sarachana T.
      • Zhou R.
      • Chen G.
      • Manji H.K.
      • Hu V.W.
      Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines.
      ); Ghahramani Seno et al., 2011 (
      • Ghahramani Seno M.M.
      • Hu P.
      • Gwadry F.G.
      • Pinto D.
      • Marshall C.R.
      • Casallo G.
      • et al.
      Gene and miRNA expression profiles in autism spectrum disorders.
      )
      Bipolar DisordermiR-19aKannu et al., 2013 (
      • Kannu P.
      • Campos-Xavier A.B.
      • Hull D.
      • Martinet D.
      • Ballhausen D.
      • Bonafe L.
      Post-axial polydactyly type A2, overgrowth and autistic traits associated with a chromosome 13q31.3 microduplication encompassing miR-17-92 and GPC5.
      ); Hemmat et al., 2014 (
      • Hemmat M.
      • Rumple M.J.
      • Mahon L.W.
      • Strom C.M.
      • Anguiano A.
      • Talai M.
      • et al.
      Short stature, digit anomalies and dysmorphic facial features are associated with the duplication of miR-17 ~ 92 cluster.
      )
      let-7bMiller et al., 2012 (
      • Miller B.H.
      • Zeier Z.
      • Xi L.
      • Lanz T.A.
      • Deng S.
      • Strathmann J.
      • et al.
      MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function.
      ); Shih et al., 2012 (
      • Shih W.L.
      • Kao C.F.
      • Chuang L.C.
      • Kuo P.H.
      Incorporating information of microRNAs into pathway analysis in a genome-wide association study of bipolar disorder.
      )
      miR-19b-1Kannu et al., 2013 (
      • Kannu P.
      • Campos-Xavier A.B.
      • Hull D.
      • Martinet D.
      • Ballhausen D.
      • Bonafe L.
      Post-axial polydactyly type A2, overgrowth and autistic traits associated with a chromosome 13q31.3 microduplication encompassing miR-17-92 and GPC5.
      ); Hemmat et al., 2014 (
      • Hemmat M.
      • Rumple M.J.
      • Mahon L.W.
      • Strom C.M.
      • Anguiano A.
      • Talai M.
      • et al.
      Short stature, digit anomalies and dysmorphic facial features are associated with the duplication of miR-17 ~ 92 cluster.
      )
      miR-106b
      MiRNA has been identified multiple times in more than one of these conditions.
      Moreau et al., 2011 (
      • Moreau M.P.
      • Bruse S.E.
      • David-Rus R.
      • Buyske S.
      • Brzustowicz L.M.
      Altered microRNA expression profiles in postmortem brain samples from individuals with schizophrenia and bipolar disorder.
      ); Shih et al., 2012 (
      • Shih W.L.
      • Kao C.F.
      • Chuang L.C.
      • Kuo P.H.
      Incorporating information of microRNAs into pathway analysis in a genome-wide association study of bipolar disorder.
      ); Smalheiser et al., 2014 (
      • Smalheiser N.R.
      • Lugli G.
      • Zhang H.
      • Rizavi H.
      • Cook E.H.
      • Dwivedi Y.
      Expression of microRNAs and other small RNAs in prefrontal cortex in schizophrenia, bipolar disorder and depressed subjects.
      )
      miR-200aVaishnavi et al., 2013 (
      • Vaishnavi V.
      • Manikandan M.
      • Tiwary B.K.
      • Munirajan A.K.
      Insights on the functional impact of microRNAs present in autism-associated copy number variants.
      ); Marrale et al., 2014 (
      • Marrale M.
      • Albanese N.N.
      • Cali F.
      • Romano V.
      Assessing the impact of copy number variants on miRNA genes in autism by Monte Carlo simulation.
      )
      miR-132
      MiRNA has been identified multiple times in more than one of these conditions.
      Miller et al., 2012 (
      • Miller B.H.
      • Zeier Z.
      • Xi L.
      • Lanz T.A.
      • Deng S.
      • Strathmann J.
      • et al.
      MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function.
      ); Whalley et al., 2012 (
      • Whalley H.C.
      • Papmeyer M.
      • Romaniuk L.
      • Sprooten E.
      • Johnstone E.C.
      • Hall J.
      • et al.
      Impact of a microRNA MIR137 susceptibility variant on brain function in people at high genetic risk of schizophrenia or bipolar disorder.
      )
      miR-200bVaishnavi et al., 2013 (
      • Vaishnavi V.
      • Manikandan M.
      • Tiwary B.K.
      • Munirajan A.K.
      Insights on the functional impact of microRNAs present in autism-associated copy number variants.
      ); Marrale et al., 2014 (
      • Marrale M.
      • Albanese N.N.
      • Cali F.
      • Romano V.
      Assessing the impact of copy number variants on miRNA genes in autism by Monte Carlo simulation.
      )
      miR-133bKim et al., 2010 (
      • Kim A.H.
      • Reimers M.
      • Maher B.
      • Williamson V.
      • McMichael O.
      • McClay J.L.
      • et al.
      MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders.
      ); Shih et al., 2012 (
      • Shih W.L.
      • Kao C.F.
      • Chuang L.C.
      • Kuo P.H.
      Incorporating information of microRNAs into pathway analysis in a genome-wide association study of bipolar disorder.
      )
      miR-20aKannu et al., 2013 (
      • Kannu P.
      • Campos-Xavier A.B.
      • Hull D.
      • Martinet D.
      • Ballhausen D.
      • Bonafe L.
      Post-axial polydactyly type A2, overgrowth and autistic traits associated with a chromosome 13q31.3 microduplication encompassing miR-17-92 and GPC5.
      ); Hemmat et al., 2014 (
      • Hemmat M.
      • Rumple M.J.
      • Mahon L.W.
      • Strom C.M.
      • Anguiano A.
      • Talai M.
      • et al.
      Short stature, digit anomalies and dysmorphic facial features are associated with the duplication of miR-17 ~ 92 cluster.
      )
      miR-145
      MiRNA has been identified multiple times in more than one of these conditions.
      Kim et al., 2010 (
      • Kim A.H.
      • Reimers M.
      • Maher B.
      • Williamson V.
      • McMichael O.
      • McClay J.L.
      • et al.
      MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders.
      ); Smalheiser et al., 2014 (
      • Smalheiser N.R.
      • Lugli G.
      • Zhang H.
      • Rizavi H.
      • Cook E.H.
      • Dwivedi Y.
      Expression of microRNAs and other small RNAs in prefrontal cortex in schizophrenia, bipolar disorder and depressed subjects.
      )
      miR-211Miller et al., 2009 (
      • Miller D.T.
      • Shen Y.
      • Weiss L.A.
      • Korn J.
      • Anselm I.
      • Bridgemohan C.
      • et al.
      Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders.
      ); Sarachana et al., 2010 (
      • Sarachana T.
      • Zhou R.
      • Chen G.
      • Manji H.K.
      • Hu V.W.
      Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines.
      ); Vaishnavi et al., 2013 (
      • Vaishnavi V.
      • Manikandan M.
      • Tiwary B.K.
      • Munirajan A.K.
      Insights on the functional impact of microRNAs present in autism-associated copy number variants.
      )
      miR-148b
      MiRNA has been identified multiple times in more than one of these conditions.
      Moreau et al., 2011 (
      • Moreau M.P.
      • Bruse S.E.
      • David-Rus R.
      • Buyske S.
      • Brzustowicz L.M.
      Altered microRNA expression profiles in postmortem brain samples from individuals with schizophrenia and bipolar disorder.
      ); Shih et al., 2012 (
      • Shih W.L.
      • Kao C.F.
      • Chuang L.C.
      • Kuo P.H.
      Incorporating information of microRNAs into pathway analysis in a genome-wide association study of bipolar disorder.
      )
      miR-23aAbu-Elneel et al., 2008 (
      • Abu-Elneel K.
      • Liu T.
      • Gazzaniga F.S.
      • Nishimura Y.
      • Wall D.P.
      • Geschwind D.H.
      • et al.
      Heterogeneous dysregulation of microRNAs across the autism spectrum.
      ); Talebizadeh et al., 2008 (
      • Talebizadeh Z.
      • Butler M.G.
      • Theodoro M.F.
      Feasibility and relevance of examining lymphoblastoid cell lines to study role of microRNAs in autism.
      ); Sarachana et al., 2010 (
      • Sarachana T.
      • Zhou R.
      • Chen G.
      • Manji H.K.
      • Hu V.W.
      Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines.
      )
      miR-15aaMoreau et al., 2011 (
      • Moreau M.P.
      • Bruse S.E.
      • David-Rus R.
      • Buyske S.
      • Brzustowicz L.M.
      Altered microRNA expression profiles in postmortem brain samples from individuals with schizophrenia and bipolar disorder.
      ); Shih et al., 2012 (
      • Shih W.L.
      • Kao C.F.
      • Chuang L.C.
      • Kuo P.H.
      Incorporating information of microRNAs into pathway analysis in a genome-wide association study of bipolar disorder.
      )
      miR-320aAbu-Elneel et al., 2008 (
      • Abu-Elneel K.
      • Liu T.
      • Gazzaniga F.S.
      • Nishimura Y.
      • Wall D.P.
      • Geschwind D.H.
      • et al.
      Heterogeneous dysregulation of microRNAs across the autism spectrum.
      ); Talebizadeh et al., 2008 (
      • Talebizadeh Z.
      • Butler M.G.
      • Theodoro M.F.
      Feasibility and relevance of examining lymphoblastoid cell lines to study role of microRNAs in autism.
      )
      miR-17
      MiRNA has been identified multiple times in more than one of these conditions.
      Shih et al., 2012 (
      • Shih W.L.
      • Kao C.F.
      • Chuang L.C.
      • Kuo P.H.
      Incorporating information of microRNAs into pathway analysis in a genome-wide association study of bipolar disorder.
      ); Smalheiser et al., 2014 (
      • Smalheiser N.R.
      • Lugli G.
      • Zhang H.
      • Rizavi H.
      • Cook E.H.
      • Dwivedi Y.
      Expression of microRNAs and other small RNAs in prefrontal cortex in schizophrenia, bipolar disorder and depressed subjects.
      )
      miR-429Vaishnavi et al., 2013 (
      • Vaishnavi V.
      • Manikandan M.
      • Tiwary B.K.
      • Munirajan A.K.
      Insights on the functional impact of microRNAs present in autism-associated copy number variants.
      ); Marrale et al., 2014 (
      • Marrale M.
      • Albanese N.N.
      • Cali F.
      • Romano V.
      Assessing the impact of copy number variants on miRNA genes in autism by Monte Carlo simulation.
      )
      miR-27bMoreau et al., 2011 (
      • Moreau M.P.
      • Bruse S.E.
      • David-Rus R.
      • Buyske S.
      • Brzustowicz L.M.
      Altered microRNA expression profiles in postmortem brain samples from individuals with schizophrenia and bipolar disorder.
      ); Shih et al., 2012 (
      • Shih W.L.
      • Kao C.F.
      • Chuang L.C.
      • Kuo P.H.
      Incorporating information of microRNAs into pathway analysis in a genome-wide association study of bipolar disorder.
      )
      miR-484Abu-Elneel et al., 2008 (
      • Abu-Elneel K.
      • Liu T.
      • Gazzaniga F.S.
      • Nishimura Y.
      • Wall D.P.
      • Geschwind D.H.
      • et al.
      Heterogeneous dysregulation of microRNAs across the autism spectrum.
      ); Vaishnavi et al., 2013 (
      • Vaishnavi V.
      • Manikandan M.
      • Tiwary B.K.
      • Munirajan A.K.
      Insights on the functional impact of microRNAs present in autism-associated copy number variants.
      )
      miR-29aaKim et al., 2010 (
      • Kim A.H.
      • Reimers M.
      • Maher B.
      • Williamson V.
      • McMichael O.
      • McClay J.L.
      • et al.
      MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders.
      ); Shih et al., 2012 (
      • Shih W.L.
      • Kao C.F.
      • Chuang L.C.
      • Kuo P.H.
      Incorporating information of microRNAs into pathway analysis in a genome-wide association study of bipolar disorder.
      )
      miR-598Abu-Elneel et al., 2008 (
      • Abu-Elneel K.
      • Liu T.
      • Gazzaniga F.S.
      • Nishimura Y.
      • Wall D.P.
      • Geschwind D.H.
      • et al.
      Heterogeneous dysregulation of microRNAs across the autism spectrum.
      ); Vaishnavi et al., 2013 (
      • Vaishnavi V.
      • Manikandan M.
      • Tiwary B.K.
      • Munirajan A.K.
      Insights on the functional impact of microRNAs present in autism-associated copy number variants.
      )
      miR-29cShih et al., 2012 (
      • Shih W.L.
      • Kao C.F.
      • Chuang L.C.
      • Kuo P.H.
      Incorporating information of microRNAs into pathway analysis in a genome-wide association study of bipolar disorder.
      ); Banigan et al., 2013 (
      • Banigan M.G.
      • Kao P.F.
      • Kozubek J.A.
      • Winslow A.R.
      • Medina J.
      • Costa J.
      • et al.
      Differential expression of exosomal microRNAs in prefrontal cortices of schizophrenia and bipolar disorder patients.
      ); Smalheiser et al., 2014 (
      • Smalheiser N.R.
      • Lugli G.
      • Zhang H.
      • Rizavi H.
      • Cook E.H.
      • Dwivedi Y.
      Expression of microRNAs and other small RNAs in prefrontal cortex in schizophrenia, bipolar disorder and depressed subjects.
      )
      miR-649Vaishnavi et al., 2013 (
      • Vaishnavi V.
      • Manikandan M.
      • Tiwary B.K.
      • Munirajan A.K.
      Insights on the functional impact of microRNAs present in autism-associated copy number variants.
      ); Marrale et al., 2014 (
      • Marrale M.
      • Albanese N.N.
      • Cali F.
      • Romano V.
      Assessing the impact of copy number variants on miRNA genes in autism by Monte Carlo simulation.
      )
      miR-874Kim et al., 2010 (
      • Kim A.H.
      • Reimers M.
      • Maher B.
      • Williamson V.
      • McMichael O.
      • McClay J.L.
      • et al.
      MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders.
      ); Miller et al., 2012 (
      • Miller B.H.
      • Zeier Z.
      • Xi L.
      • Lanz T.A.
      • Deng S.
      • Strathmann J.
      • et al.
      MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function.
      )
      miR-650Ghahramani Seno et al., 2011 (
      • Ghahramani Seno M.M.
      • Hu P.
      • Gwadry F.G.
      • Pinto D.
      • Marshall C.R.
      • Casallo G.
      • et al.
      Gene and miRNA expression profiles in autism spectrum disorders.
      ); Marrale et al., 2014 (
      • Marrale M.
      • Albanese N.N.
      • Cali F.
      • Romano V.
      Assessing the impact of copy number variants on miRNA genes in autism by Monte Carlo simulation.
      )
      miR-92a-1Kannu et al., 2013 (
      • Kannu P.
      • Campos-Xavier A.B.
      • Hull D.
      • Martinet D.
      • Ballhausen D.
      • Bonafe L.
      Post-axial polydactyly type A2, overgrowth and autistic traits associated with a chromosome 13q31.3 microduplication encompassing miR-17-92 and GPC5.
      ); Hemmat et al., 2014 (
      • Hemmat M.
      • Rumple M.J.
      • Mahon L.W.
      • Strom C.M.
      • Anguiano A.
      • Talai M.
      • et al.
      Short stature, digit anomalies and dysmorphic facial features are associated with the duplication of miR-17 ~ 92 cluster.
      )
      miR-93Abu-Elneel et al., 2008 (
      • Abu-Elneel K.
      • Liu T.
      • Gazzaniga F.S.
      • Nishimura Y.
      • Wall D.P.
      • Geschwind D.H.
      • et al.
      Heterogeneous dysregulation of microRNAs across the autism spectrum.
      ); Sarachana et al., 2010 (
      • Sarachana T.
      • Zhou R.
      • Chen G.
      • Manji H.K.
      • Hu V.W.
      Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines.
      )
      These miRNAs have been associated with schizophrenia, bipolar disorder, major depressive disorder, or autism spectrum disorders by more than one study.
      miRNA, microRNA.
      a MiRNA has been identified multiple times in more than one of these conditions.
      Although these analyses suggest that miRNAs are important in the etiology of SZ, there is significant heterogeneity and some direct conflicts among studies. For example, in contrast to the study by Perkins et al. (
      • Perkins D.O.
      • Jeffries C.D.
      • Jarskog L.F.
      • Thomson J.M.
      • Woods K.
      • Newman M.A.
      • et al.
      microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder.
      ), we observed miR-26b, miR-29c, and miR-195 to be upregulated in BA9 (
      • Beveridge N.J.
      • Gardiner E.
      • Carroll A.P.
      • Tooney P.A.
      • Cairns M.J.
      Schizophrenia is associated with an increase in cortical microRNA biogenesis.
      ). Kim et al. (
      • Kim A.H.
      • Reimers M.
      • Maher B.
      • Williamson V.
      • McMichael O.
      • McClay J.L.
      • et al.
      MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders.
      ) also analyzed postmortem tissue from the DLPFC (BA46) using a TaqMan Low Density Array (TLDA; Applied Biosystems Waltham, Massachusetts) and observed a discrepancy among individuals concerning the direction of dysregulation. On average, however, they discovered seven miRNAs were significantly upregulated (miR-34a, miR-132, miR-132*, miR-212, miR-544, miR-7, and miR-154*). In contrast, miR-212 was observed to be downregulated by Perkins et al. (
      • Perkins D.O.
      • Jeffries C.D.
      • Jarskog L.F.
      • Thomson J.M.
      • Woods K.
      • Newman M.A.
      • et al.
      microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder.
      ). The dysregulation of miR-312 and miR-212 is also particularly significant because these miRNAs are part of a cluster that has been identified in other psychiatric disorders. These miRNAs also have known functions in the brain, including regulating synaptic transmission and plasticity in the hippocampus and neocortex (
      • Remenyi J.
      • van den Bosch M.W.
      • Palygin O.
      • Mistry R.B.
      • McKenzie C.
      • Macdonald A.
      • et al.
      miR-132/212 knockout mice reveal roles for these miRNAs in regulating cortical synaptic transmission and plasticity.
      ) and regulating memory formation (
      • Wang R.Y.
      • Phang R.Z.
      • Hsu P.H.
      • Wang W.H.
      • Huang H.T.
      • Liu I.Y.
      In vivo knockdown of hippocampal miR-132 expression impairs memory acquisition of trace fear conditioning.
      ). These miRNAs have been the focus of many studies and have particular relevance to SZ and MDD (Supplement 1). Other miRNAs species have also been associated with SZ and other psychiatric disorders on multiple occasions (Table 1), and despite conflicting findings, patterns are emerging with significance to SZ.
      Analysis of miRNA expression in peripheral tissues has also revealed associations with SZ. We explored miRNA expression in peripheral blood mononuclear cells using a microarray and qRT-PCR and observed 83 downregulated miRNAs in SZ with a false discovery rate <5% (
      • Gardiner E.
      • Beveridge N.J.
      • Wu J.Q.
      • Carr V.
      • Scott R.J.
      • Tooney P.A.
      • et al.
      Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells.
      ). Of these, 17 came from the imprinted DLK1-DIO3 region at the 14q32 locus and are part of many maternally expressed miRNA clusters in the region (
      • Royo H.
      • Cavaille J.
      Non-coding RNAs in imprinted gene clusters.
      ). Transcription of the larger miR-379/410 cluster is induced by neuronal activity, suggesting their importance in neuronal function (
      • Fiore R.
      • Khudayberdiev S.
      • Christensen M.
      • Siegel G.
      • Flavell S.W.
      • Kim T.K.
      • et al.
      Mef2-mediated transcription of the miR379-410 cluster regulates activity-dependent dendritogenesis by fine-tuning Pumilio2 protein levels.
      ). In a similar study, Lai et al. (
      • Lai C.Y.
      • Yu S.L.
      • Hsieh M.H.
      • Chen C.H.
      • Chen H.Y.
      • Wen C.C.
      • et al.
      MicroRNA expression aberration as potential peripheral blood biomarkers for schizophrenia.
      ) observed six upregulated miRNAs by TLDA and qRT-PCR, including miR-449a, miR-564, miR-432, miR-548, miR-572, and miR-652, and one downregulated miRNA (miR-34a). In an analysis of serum miRNA expression by qRT-PCR, Shi et al. (
      • Shi W.
      • Du J.
      • Qi Y.
      • Liang G.
      • Wang T.
      • Li S.
      • et al.
      Aberrant expression of serum miRNAs in schizophrenia.
      ) found miR-195 downregulated, whereas miR-181b, miR-219-2-3p, miR-1308, and let-7g were upregulated. These studies demonstrate the potential of peripheral biomarkers for psychiatric disease.
      Numerous SNPs in miRNA genes have been associated with SZ. In one of the largest genome-wide association studies of SZ undertaken by the Psychiatric Genome Consortium, with 17,836 cases and 33,859 controls, the SNP rs1625579 within the intron for a putative primary transcript of miR-137 was the strongest new association with SZ (
      • Ripke S.
      • Sanders A.
      • Kendler K.
      • Levinson D.
      • Sklar P.
      • Holmans P.
      • et al.
      Genome-wide association study identifies five new schizophrenia loci.
      ). Four other loci associated with SZ in the same study were also predicted targets of miR-137, supporting the functional significance of this regulatory network in SZ. More recently, the Psychiatric Genome Consortium confirmed the association within the MIR548AJ2 gene in 36,989 cases and 113,075 controls (
      • Ripke S.
      • Neale B.M.
      • Corvin A.
      • Walters J.T.R.
      • Farh K.-H.
      • Holmans P.A.
      • et al.
      Biological insights from 108 schizophrenia-associated genetic loci.
      ). Further research into miR-137 revealed numerous functional implications relevant to the etiology of SZ, including a role in proliferation and differentiation of neuronal stem cells in the developing brain (
      • Sun G.
      • Ye P.
      • Murai K.
      • Lang M.F.
      • Li S.
      • Zhang H.
      • et al.
      miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells.
      ) and roles in glutamatergic and GABAergic signaling and long-term potentiation (
      • Wright C.
      • Turner J.A.
      • Calhoun V.D.
      • Perrone-Bizzozero N.
      Potential impact of miR-137 and its targets in schizophrenia.
      ). The risk allele rs1625579 has been observed to correspond with reduced miR-137 expression in the DLPFC and hyperactivation of this region (Supplement 1) (
      • Guella I.
      • Sequeira A.
      • Rollins B.
      • Morgan L.
      • Torri F.
      • van Erp T.G.
      • et al.
      Analysis of miR-137 expression and rs1625579 in dorsolateral prefrontal cortex.
      ,
      • van Erp T.G.
      • Guella I.
      • Vawter M.P.
      • Turner J.
      • Brown G.G.
      • McCarthy G.
      • et al.
      Schizophrenia miR-137 locus risk genotype is associated with dorsolateral prefrontal cortex hyperactivation.
      ). Another SZ-associated SNP, rs3822674, has been identified and found to affect a binding site of miR-498 in the 3′ untranslated region of complexin 2 (CPLX2) (
      • Begemann M.
      • Grube S.
      • Papiol S.
      • Malzahn D.
      • Krampe H.
      • Ribbe K.
      • et al.
      Modification of cognitive performance in schizophrenia by complexin 2 gene polymorphisms.
      ). Using a luciferase assay, the T allele at this SNP was found to induce translational repression in the presence of miR-498, whereas the C allele prevented repression. This C allele, in combination with the C and T alleles of SNPs rs1366116 and rs3892909 (also within CPLX2), was associated with the poorest cognitive performance within the study. This effect on cognitive function in mice was observed only after minor brain lesions were applied during puberty, supporting a developmental two-hit hypothesis of SZ (
      • Maynard T.M.
      • Sikich L.
      • Lieberman J.A.
      • LaMantia A.S.
      Neural development, cell-cell signaling, and the “two-hit” hypothesis of schizophrenia.
      ).
      Environmental factors can also influence miRNA levels and have implications for SZ. For example, maternal immune activation (MIA) in animals using polyriboinosinic-polyribocytidilic acid (poly-I:C) is an important tool for studying the role of maternal infections in pathophysiology of SZ and causes phenotypic abnormalities in the offspring that mimic SZ. We identified 21 miRNA species that were differentially expressed after MIA treatment in rats (
      • Hollins S.L.
      • Zavitsanou K.
      • Walker F.R.
      • Cairns M.J.
      Alteration of imprinted Dlk1-Dio3 miRNA cluster expression in the entorhinal cortex induced by maternal immune activation and adolescent cannabinoid exposure.
      ). In the same study, we treated poly-I:C control adolescent rats with the cannabinoid receptor (CB1) agonist HU210 as a model for human adolescent cannabis exposure and observed dysregulation of seven miRNA species, most of which were also observed to be dysregulated in the MIA group. Finally, a two-hit model in which poly-I:C-affected rats were exposed to HU210 during adolescence produced 18 differentially expressed miRNA species. Target prediction of these 18 miRNAs revealed potential roles in mitogen-activated protein kinase signaling, important for neuronal development and cognition (
      • Samuels I.S.
      • Karlo J.C.
      • Faruzzi A.N.
      • Pickering K.
      • Herrup K.
      • Sweatt J.D.
      • et al.
      Deletion of ERK2 mitogen-activated protein kinase identifies its key roles in cortical neurogenesis and cognitive function.
      ), and the Wnt signaling pathway, also important in neuronal development and SZ (
      • Miyaoka T.
      • Seno H.
      • Ishino H.
      Increased expression of Wnt-1 in schizophrenic brains.
      ). This study highlights the ability of environmental factors to influence miRNA expression, which may have a role to play in the etiology of SZ.

      BD

      Emerging research links miRNAs to BD with several studies showing significant alterations in miRNA expression levels in postmortem cortical brain tissue from affected individuals (Table S1 in Supplement 1). A few of these studies were run in parallel alongside SZ studies discussed in the preceding section. Kim et al. (
      • Kim A.H.
      • Reimers M.
      • Maher B.
      • Williamson V.
      • McMichael O.
      • McClay J.L.
      • et al.
      MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders.
      ) used another TLDA array to analyze postmortem DLPFC tissue samples of individuals with BD and healthy control subjects (BA46) and identified seven miRNAs (miR-504, miR-145, miR-145*, miR-22*, miR-133b, miR-154*, and miR-889) to be upregulated, with a further eight miRNAs (miR-454*, miR-29a, miR-520c-3p, miR-140-3p, miR-767-5p, miR-874, miR-32, and miR-573) downregulated in individuals with BD compared with control subjects. Moreau et al. (
      • Moreau M.P.
      • Bruse S.E.
      • David-Rus R.
      • Buyske S.
      • Brzustowicz L.M.
      Altered microRNA expression profiles in postmortem brain samples from individuals with schizophrenia and bipolar disorder.
      ) also analyzed miRNA expression in BD with multiplexed qRT-PCR alongside their SZ study and found a slight trend toward downregulation of miRNA expression, with 24 miRNAs downregulated in the prefrontal cortex (BA9). By contrast, Miller et al. (
      • Miller B.H.
      • Zeier Z.
      • Xi L.
      • Lanz T.A.
      • Deng S.
      • Strathmann J.
      • et al.
      MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function.
      ) observed the opposite in their microarray analysis of BA46, with 10 miRNAs upregulated. More recently, Smalheiser et al. (
      • Smalheiser N.R.
      • Lugli G.
      • Zhang H.
      • Rizavi H.
      • Cook E.H.
      • Dwivedi Y.
      Expression of microRNAs and other small RNAs in prefrontal cortex in schizophrenia, bipolar disorder and depressed subjects.
      ) reported a fairly balanced distribution using a TLDA array, with four miRNAs upregulated and five miRNAs downregulated. Banigan et al. (
      • Banigan M.G.
      • Kao P.F.
      • Kozubek J.A.
      • Winslow A.R.
      • Medina J.
      • Costa J.
      • et al.
      Differential expression of exosomal microRNAs in prefrontal cortices of schizophrenia and bipolar disorder patients.
      ) analyzed the miRNA content of exosomes from DLPFC (BA9) with a Luminex Multiplex Assay (Luminex Corporation, Austin, Texas) and qRT-PCR validation and discovered just one miRNA, miR-29c, to be upregulated. The SNP rs1625579, which affects miR-137 in SZ, was also found to be functionally associated with individuals at risk of BD (
      • Whalley H.C.
      • Papmeyer M.
      • Romaniuk L.
      • Sprooten E.
      • Johnstone E.C.
      • Hall J.
      • et al.
      Impact of a microRNA MIR137 susceptibility variant on brain function in people at high genetic risk of schizophrenia or bipolar disorder.
      ).
      Although there is no direct evidence of dysregulated miRNA biogenesis in BD, valproic acid has been shown to induce proteasomal degradation of Dicer, which causes a general downregulation of miRNA expression (
      • Zhang Z.
      • Convertini P.
      • Shen M.
      • Xu X.
      • Lemoine F.
      • de la Grange P.
      • et al.
      Valproic acid causes proteasomal degradation of DICER and influences miRNA expression.
      ). These observations suggest that this mood stabilizer used for treatment of BD may have some influence on psychopathology through the modification of miRNA biogenesis.
      Despite substantial heterogeneity of miRNA identified in association with BD, a few miRNAs have appeared in multiple studies (Table 1). Several of these miRNAs, including miR-29c, miR-132, and miR-106b, have also been associated with SZ suggesting there may be common pathways that are affected by small RNA molecules in these psychotic syndromes. In particular, miR-132, mentioned earlier, has been implicated in the circadian clock machinery, which is associated with BD and depression (Supplement 1) (
      • Etain B.
      • Jamain S.
      • Milhiet V.
      • Lajnef M.
      • Boudebesse C.
      • Dumaine A.
      • et al.
      Association between circadian genes, bipolar disorders and chronotypes.
      ). Further investigation of these more robust miRNAs and their target genes should provide insight into the development these disorders, and these miRNAs could potentially serve as biomarkers and new drug targets.

      MDD

      The dysregulation of miRNAs has also been linked to MDD in recent years (Table S1 in Supplement 1). One of the earliest pieces of evidence for this link was the association between depression and a SNP in the P2RX7 (purinergic receptor P2x, ligand-gated ion channel 7) gene (
      • Rahman O.A.
      • Sasvari-Szekely M.
      • Szekely A.
      • Faludi G.
      • Guttman A.
      • Nemoda Z.
      Analysis of a polymorphic microRNA target site in the purinergic receptor P2RX7 gene.
      ), which is reportedly involved in modulating synaptic neurotransmission (
      • Sperlagh B.
      • Vizi E.S.
      • Wirkner K.
      • Illes P.
      P2X7 receptors in the nervous system.
      ). This SNP, rs1653625, occurs in the putative miRNA target site of miR-1302 and miR-625 within the P2RX7 3′ untranslated region. Other SNPs associated with MDD by genotyping include ss178077483, which is within the pre–miR-30e gene and is associated with a longer P300 waveform latency, a correlate of slower cognitive functioning (
      • Xu Y.
      • Liu H.
      • Li F.
      • Sun N.
      • Ren Y.
      • Liu Z.
      • et al.
      A polymorphism in the microRNA-30e precursor associated with major depressive disorder risk and P300 waveform.
      ), and two others in the miRNA pathway genes AGO1 (Argonaute 1) (rs636832) and DGCR8 (rs3757) (
      • He Y.
      • Zhou Y.
      • Xi Q.
      • Cui H.
      • Luo T.
      • Song H.
      • et al.
      Genetic variations in microRNA processing genes are associated with susceptibility in depression.
      ). This link between miRNA pathway gene polymorphisms and depression is particularly interesting because a postmortem TLDA array study found a global downregulation of miRNA species within BA9 of the DLPFC in subjects exhibiting depression and suicidality (
      • Smalheiser N.R.
      • Lugli G.
      • Rizavi H.S.
      • Torvik V.I.
      • Turecki G.
      • Dwivedi Y.
      MicroRNA expression is down-regulated and reorganized in prefrontal cortex of depressed suicide subjects.
      ). Although this global downregulation hints at the possibility for alterations in miRNA processing in the pathophysiology of depression, no changes in miRNA processing or DGCR8, DROSHA, or DICER messenger RNA expression were observed.
      A mouse model established in the same laboratory assessed the difference in miRNA expression profiles between mice that showed learned helplessness—an analogue for depressive symptoms—and mice that did not show learned helplessness compared with controls after repeated, inescapable shock using another TLDA array approach (
      • Smalheiser N.R.
      • Lugli G.
      • Rizavi H.S.
      • Zhang H.
      • Torvik V.I.
      • Pandey G.N.
      • et al.
      MicroRNA expression in rat brain exposed to repeated inescapable shock: Differential alterations in learned helplessness vs. non-learned helplessness.
      ). The authors found that the mice that did not show learned helplessness demonstrated a significant global downregulation of miRNA expression as an adaptive response, whereas mice that did show learned helplessness did not demonstrate downregulation. The miRNAs included miR-96, miR-141, miR-182, miR-183, miR-298, miR-200a/b/c, miR-322, and miR-429. Three of these molecules, miR-96, miR-182, and miR-183, are part of a polycistronic miRNA cluster that may be involved in regulating genes in step with the circadian clock (
      • Xu S.
      • Witmer P.D.
      • Lumayag S.
      • Kovacs B.
      • Valle D.
      MicroRNA (miRNA) transcriptome of mouse retina and identification of a sensory organ-specific miRNA cluster.
      ); this is significant because disruption of the circadian rhythms is thought to be a factor in many disorders, including depression (
      • Mendlewicz J.
      Disruption of the circadian timing systems: Molecular mechanisms in mood disorders.
      ). Taken together, these studies may suggest that depressive symptoms brought about by excessive stress are a result of a disrupted circadian clock via the perturbation of its regulation by miRNAs.
      As mentioned earlier, miR-132 has been associated with many psychiatric illnesses. In one study, qRT-PCR analysis found increased serum levels of miR-132 and miR-182 in patients with depression (
      • Li Y.J.
      • Xu M.
      • Gao Z.H.
      • Wang Y.Q.
      • Yue Z.
      • Zhang Y.X.
      • et al.
      Alterations of serum levels of BDNF-related miRNAs in patients with depression.
      ). In addition, both miRNAs are capable of downregulating brain-derived neurotrophic factor, which was found at lower serum levels in the patients with depression by enzyme-linked immunosorbent assay. The interaction of miR-132 with brain-derived neurotrophic factor as well as with cyclic adenosine monophosphate response element binding protein and glucocorticoids has been proposed to have a significant role in the development of some cases of depression as well as the comorbidity of cardiovascular diseases with depression (
      • Zheng Z.
      • Zeng Y.
      • Huang H.
      • Xu F.
      MicroRNA-132 may play a role in coexistence of depression and cardiovascular disease: A hypothesis.
      ). Also, miR-132 has been implicated in regulating the circadian clock (
      • Cheng H.Y.
      • Papp J.W.
      • Varlamova O.
      • Dziema H.
      • Russell B.
      • Curfman J.P.
      • et al.
      microRNA modulation of circadian-clock period and entrainment.
      ), which is thought to be important in MDD.

      ASDs

      Direct evidence for miRNA involvement in ASDs is currently very sparse; only a few studies have associated altered miRNA expression levels in biological tissues with the incidence of autistic traits (Table S1 in Supplement 1). One study identified 28 miRNA species that were dysregulated in postmortem cerebellar cortex tissue in at least 1 of 13 subjects (
      • Abu-Elneel K.
      • Liu T.
      • Gazzaniga F.S.
      • Nishimura Y.
      • Wall D.P.
      • Geschwind D.H.
      • et al.
      Heterogeneous dysregulation of microRNAs across the autism spectrum.
      ). Among these miRNAs were miR-15a/b, miR-132, miR-212, and miR-106b, which were mentioned previously in relation to SZ and mood disorders. However, there has been some contention over the validity of these data (
      • Buyske S.
      Comment on the article “Heterogeneous dysregulation of microRNAs across the autism spectrum” by Abu-Elneel et al.
      ). Three other studies investigated miRNA expression levels in lymphoblastoid cells by microarray analysis and found differentially expressed miRNA species associated with autism (
      • Talebizadeh Z.
      • Butler M.G.
      • Theodoro M.F.
      Feasibility and relevance of examining lymphoblastoid cell lines to study role of microRNAs in autism.
      ,
      • Sarachana T.
      • Zhou R.
      • Chen G.
      • Manji H.K.
      • Hu V.W.
      Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines.
      ,
      • Ghahramani Seno M.M.
      • Hu P.
      • Gwadry F.G.
      • Pinto D.
      • Marshall C.R.
      • Casallo G.
      • et al.
      Gene and miRNA expression profiles in autism spectrum disorders.
      ). The findings reported by Sarachana et al. (
      • Sarachana T.
      • Zhou R.
      • Chen G.
      • Manji H.K.
      • Hu V.W.
      Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines.
      ) included the dysregulation of miR-107, miR-195, and miR-106b, which were also observed to be dysregulated in SZ. These studies not only present a case for miRNA involvement in ASDs, but they also further highlight the importance of a few miRNAs that may be common to a range of psychiatric disorders.
      In addition to these findings, a few studies have linked CNVs of miRNA genes to ASDs and autistic traits. Two of these studies identified the microduplication of the miR-17-92 cluster on chromosome 13q31.3—containing miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, and miR-92a-1—in patients with autistic traits (
      • Hemmat M.
      • Rumple M.J.
      • Mahon L.W.
      • Strom C.M.
      • Anguiano A.
      • Talai M.
      • et al.
      Short stature, digit anomalies and dysmorphic facial features are associated with the duplication of miR-17 ~ 92 cluster.
      ,
      • Kannu P.
      • Campos-Xavier A.B.
      • Hull D.
      • Martinet D.
      • Ballhausen D.
      • Bonafe L.
      Post-axial polydactyly type A2, overgrowth and autistic traits associated with a chromosome 13q31.3 microduplication encompassing miR-17-92 and GPC5.
      ). Autistic traits also have been associated with miR-211 deletions and duplications at chromosome 15q13.2-q13.3 (
      • Miller D.T.
      • Shen Y.
      • Weiss L.A.
      • Korn J.
      • Anselm I.
      • Bridgemohan C.
      • et al.
      Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders.
      ). Finally, two groups of investigators used CNV database searches and reported a large number of miRNAs, including miR-211, that overlap with known autism-associated CNVs (
      • Vaishnavi V.
      • Manikandan M.
      • Tiwary B.K.
      • Munirajan A.K.
      Insights on the functional impact of microRNAs present in autism-associated copy number variants.
      ,
      • Marrale M.
      • Albanese N.N.
      • Cali F.
      • Romano V.
      Assessing the impact of copy number variants on miRNA genes in autism by Monte Carlo simulation.
      ). Again, miR-132 has been associated with autism disorders several times, suggesting it could be a particularly important miRNA (Supplement 1).

      Discussion

      This review has highlighted the current evidence for aberrant miRNA expression or function in four major neuropsychiatric syndromes. Many of the miRNA species identified in these studies have been characterized with regard to their functional roles within neurons and their contribution to brain function. Several miRNA species associated with these conditions are involved in proliferation, differentiation, and maturation of neurons, and their dysfunction may contribute to the neurodevelopmental deficits seen in disorders such as SZ and ASDs. Other miRNA species have roles in synaptic function and may contribute to deficits in glutamate and GABAergic signaling seen in SZ, whereas still others, including miR-132, are involved in the circadian clock pathways and have implications for mood disorders. In addition, miR-132 and a few other miRNA species have been associated with multiple conditions on several occasions, making them particularly interesting focal points for future research and possibly making them useful in a clinical context.

      Clinical Implications

      There are two potential clinical applications of miRNAs: as a diagnostic tool and as novel treatments. As discussed earlier, numerous studies have already associated miRNA expression in peripheral tissues with psychiatric disease. These miRNAs have the potential to be biomarkers for these conditions. Multiple studies of various psychiatric disorders have identified miRNAs such as miR-132/212 and miR-15 family members (Table 1), suggesting that these miRNAs may be particularly useful in identifying individuals at risk of psychiatric disease. However, given the wide range of miRNA species associated with these conditions and the apparent heterogeneity, the use of miRNAs as biomarkers remains a difficult proposition.
      The use of miRNAs or miRNA antagonist in the treatment of psychiatric disorders is an appealing concept, particularly as understanding about their function and roles in these conditions increases. At the present time, these approaches are limited by our capacity to deliver these molecules effectively. Some progress has been made more recently in clinical trials comprising patients with cancer receiving small interfering RNA nanoparticles, which are chemically identical to synthetic miRNAs, intravenously. These formulations successfully downregulated the target messenger RNA and protein (
      • Davis M.E.
      • Zuckerman J.E.
      • Choi C.H.
      • Seligson D.
      • Tolcher A.
      • Alabi C.A.
      • et al.
      Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles.
      ). Inhibition of miRNAs in vivo has also been successful; cardiac miR-15b expression was reduced in mice injected with anti-miR-15b oligonucleotides (
      • Hullinger T.G.
      • Montgomery R.L.
      • Seto A.G.
      • Dickinson B.A.
      • Semus H.M.
      • Lynch J.M.
      • et al.
      Inhibition of miR-15 protects against cardiac ischemic injury.
      ). Manipulating miRNA in the brain may not be as effective, as Krutzfeldt et al. (
      • Krutzfeldt J.
      • Kuwajima S.
      • Braich R.
      • Rajeev K.G.
      • Pena J.
      • Tuschl T.
      • et al.
      Specificity, duplex degradation and subcellular localization of antagomirs.
      ) discovered, with intravenous administration of anti-miR-16 unable to affect miRNA levels in the brain, whereas direct injection into the cerebral cortex was effective. Intracerebroventricular infusion of anti-miRNAs has been found to be an effective delivery route, suggesting intrathecal delivery may be an option (
      • Ouyang Y.B.
      • Lu Y.
      • Yue S.
      • Xu L.J.
      • Xiong X.X.
      • White R.E.
      • et al.
      miR-181 regulates GRP78 and influences outcome from cerebral ischemia in vitro and in vivo.
      ,
      • Yin K.J.
      • Deng Z.
      • Huang H.
      • Hamblin M.
      • Xie C.
      • Zhang J.
      • et al.
      miR-497 regulates neuronal death in mouse brain after transient focal cerebral ischemia.
      ). These studies demonstrate that miRNA or their antagonists have the potential to be used as therapeutic tools for the treatment of brain conditions, although the feasibility of their delivery in the clinic needs to be addressed.

      Future Studies

      Understanding of the role miRNAs play in brain function and psychiatric disorders is still a growing field. What is clear is that the relationship between miRNA expression and these conditions is complex; the dysregulation of numerous miRNA species appears to correlate with these disorders. Some miRNAs, such as miR-137, miR-132/212, and the miR-15 family, have been identified on multiple occasions, making them particularly interesting targets for further research.
      A better understanding of how miRNAs are differentially expressed spatially and temporally throughout development would aid in determining which miRNAs are the most important for psychiatric disorders as well as at what stages during development they contribute to disease. Some progress has been made in this regard; a recent study identified changes to the miRNA profile across brain regions and through development in samples from 18 normal individuals 4 months to 19 years old (
      • Ziats M.N.
      • Rennert O.M.
      Identification of differentially expressed microRNAs across the developing human brain.
      ). A few of the miRNAs discussed here were identified; miR-212 was downregulated from infancy to early childhood in the DLPFC, and miR-137 was downregulated in the same time frame in the cerebellar cortex. We also investigated developmental changes in genome-wide miRNA expression in the human DLPFC and found an interesting inflection of miRNA expression during adolescence (
      • Beveridge N.J.
      • Santarelli D.M.
      • Wang X.
      • Tooney P.A.
      • Webster M.J.
      • Weickert C.S.
      • et al.
      Maturation of the human dorsolateral prefrontal cortex coincides with a dynamic shift in microRNA expression.
      ). More recently, we explored the relationship between gene and miRNA expression in the developing midbrain and hindbrain of rat embryos and found significant differences in the timing of miRNA expression, particularly miR-132 and miR-137, which accorded with the cortical maturity in the two regions (
      • Hollins S.L.
      • Goldie B.J.
      • Carroll A.P.
      • Mason E.A.
      • Walker F.R.
      • Eyles D.W.
      • et al.
      Ontogeny of small RNA in the regulation of mammalian brain development.
      ). Further research in normal healthy brain tissue in this way will be invaluable for understanding how miRNAs contribute to disease. Another important question is how miRNAs associated with psychiatric disorders are localized in individual neurons. For example, localization to dendritic spines or axon terminals may suggest a role in synaptic activity or neurite growth and development. In this regard, miR-212 has been observed enriched in axons, whereas miR-137 and miR-15 family members miR-195 and miR-16 were enriched in the cell body (
      • Sasaki Y.
      • Gross C.
      • Xing L.
      • Goshima Y.
      • Bassell G.J.
      Identification of axon-enriched microRNAs localized to growth cones of cortical neurons.
      ). Dicer has been observed to localize in the cell body and dendrites and at the Golgi complex and endoplasmic reticulum of cerebellar granule neurons in vitro (
      • Barbato C.
      • Ciotti M.T.
      • Serafino A.
      • Calissano P.
      • Cogoni C.
      Dicer expression and localization in post-mitotic neurons.
      ). The combination of these high-resolution studies with the collection of data from large cohorts of postmortem samples and genetic associations will greatly enhance understanding of the role miRNAs play in neurobiology and psychiatric disorders.

      Conclusions

      Research in the past decade suggests that miRNAs have a significant role to play in the function of the brain, and their dysregulation and dysfunction may be part of the pathophysiology of psychiatric disorders, including SZ, mood disorders, and ASDs. Numerous studies have shown genetic associations of miRNA genes and targets as well as altered expression levels in these syndromes. The association of DGCR8 dysregulation with SZ and the association of SNPs in DGCR8 and AGO1 with MDD add further weight to this hypothesis of miRNA involvement in psychiatric disease, suggesting that, at least in some cases, miRNA dysregulation on a global scale via abnormal biogenesis may be involved in these conditions. The study of this relationship between miRNA function and psychiatric disease is a growing field, and much of the information to date is preliminary, with much still to be understood about the mechanisms by which these small RNA molecules may influence the development of psychiatric disease. However, these miRNAs are clearly important in posttranscriptional organization of gene network structures that are perturbed in complex disorders of the mind and may prove to be useful tools for diagnosis and treatment of these disorders.

      Acknowledgments and Disclosures

      This work was supported by the University of Newcastle Faculty of Health and Medicine and Priority Research Centre for Translational Neuroscience and Mental Health (MG), the Schizophrenia Research Institute using funding from the New South Wales Ministry of Health (MJC), and an M.C. Ainsworth Research Fellowship in Epigenetics (MJC).
      The authors report no biomedical financial interests or potential conflicts of interest.

      Appendix A. Supplementary Materials

      References

        • Du T.
        • Zamore P.D.
        microPrimer: The biogenesis and function of microRNA.
        Development. 2005; 132: 4645-4652
        • Bartel D.P.
        MicroRNAs: Genomics, biogenesis, mechanism, and function.
        Cell. 2004; 116: 281-297
        • Rodriguez A.
        • Griffiths-Jones S.
        • Ashurst J.L.
        • Bradley A.
        Identification of mammalian microRNA host genes and transcription units.
        Genome Res. 2004; 14: 1902-1910
        • Lee Y.
        • Ahn C.
        • Han J.
        • Choi H.
        • Kim J.
        • Yim J.
        • et al.
        The nuclear RNase III Drosha initiates microRNA processing.
        Nature. 2003; 425: 415-419
        • Gregory R.I.
        • Yan K.P.
        • Amuthan G.
        • Chendrimada T.
        • Doratotaj B.
        • Cooch N.
        • et al.
        The Microprocessor complex mediates the genesis of microRNAs.
        Nature. 2004; 432: 235-240
        • Gregory R.I.
        • Chendrimada T.P.
        • Cooch N.
        • Shiekhattar R.
        Human RISC couples microRNA biogenesis and posttranscriptional gene silencing.
        Cell. 2005; 123: 631-640
        • Kozomara A.
        • Griffiths-Jones S.
        miRBase: integrating microRNA annotation and deep-sequencing data.
        Nucleic Acids Res. 2011; 39: D152-D157
        • Lewis B.P.
        • Shih I.H.
        • Jones-Rhoades M.W.
        • Bartel D.P.
        • Burge C.B.
        Prediction of mammalian microRNA targets.
        Cell. 2003; 115: 787-798
        • Carroll A.P.
        • Tran N.
        • Tooney P.A.
        • Cairns M.J.
        Alternative mRNA fates identified in microRNA-associated transcriptome analysis.
        BMC Genomics. 2012; 13: 561
        • Lim L.P.
        • Lau N.C.
        • Garrett-Engele P.
        • Grimson A.
        • Schelter J.M.
        • Castle J.
        • et al.
        Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs.
        Nature. 2005; 433: 769-773
        • Giraldez A.J.
        • Cinalli R.M.
        • Glasner M.E.
        • Enright A.J.
        • Thomson J.M.
        • Baskerville S.
        • et al.
        MicroRNAs regulate brain morphogenesis in zebrafish.
        Science. 2005; 308: 833-838
        • Davis T.H.
        • Cuellar T.L.
        • Koch S.M.
        • Barker A.J.
        • Harfe B.D.
        • McManus M.T.
        • et al.
        Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus.
        J Neurosci. 2008; 28: 4322-4330
        • Cuellar T.L.
        • Davis T.H.
        • Nelson P.T.
        • Loeb G.B.
        • Harfe B.D.
        • Ullian E.
        • et al.
        Dicer loss in striatal neurons produces behavioral and neuroanatomical phenotypes in the absence of neurodegeneration.
        Proc Natl Acad Sci U S A. 2008; 105: 5614-5619
        • Perkins D.O.
        • Jeffries C.D.
        • Jarskog L.F.
        • Thomson J.M.
        • Woods K.
        • Newman M.A.
        • et al.
        microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder.
        Genome Biol. 2007; 8: R27
        • Beveridge N.J.
        • Gardiner E.
        • Carroll A.P.
        • Tooney P.A.
        • Cairns M.J.
        Schizophrenia is associated with an increase in cortical microRNA biogenesis.
        Mol Psychiatry. 2010; 15: 1176-1189
        • Beveridge N.J.
        • Tooney P.A.
        • Carroll A.P.
        • Gardiner E.
        • Bowden N.
        • Scott R.J.
        • et al.
        Dysregulation of miRNA 181b in the temporal cortex in schizophrenia.
        Hum Mol Genet. 2008; 17: 1156-1168
        • Liu C.
        • Teng Z.Q.
        • McQuate A.L.
        • Jobe E.M.
        • Christ C.C.
        • von Hoyningen-Huene S.J.
        • et al.
        An epigenetic feedback regulatory loop involving microRNA-195 and MBD1 governs neural stem cell differentiation.
        PloS One. 2013; 8: e51436
        • Moncini S.
        • Salvi A.
        • Zuccotti P.
        • Viero G.
        • Quattrone A.
        • Barlati S.
        • et al.
        The role of miR-103 and miR-107 in regulation of CDK5R1 expression and in cellular migration.
        PloS One. 2011; 6: e20038
        • Bassett A.S.
        • Chow E.W.
        • Husted J.
        • Weksberg R.
        • Caluseriu O.
        • Webb G.D.
        • et al.
        Clinical features of 78 adults with 22q11 deletion syndrome.
        Am J Med Genet A. 2005; 138: 307-313
        • Shiohama A.
        • Sasaki T.
        • Noda S.
        • Minoshima S.
        • Shimizu N.
        Molecular cloning and expression analysis of a novel gene DGCR8 located in the DiGeorge syndrome chromosomal region.
        Biochem Biophys Res Commun. 2003; 304: 184-190
        • Santarelli D.M.
        • Beveridge N.J.
        • Tooney P.A.
        • Cairns M.J.
        Upregulation of dicer and microRNA expression in the dorsolateral prefrontal cortex Brodmann area 46 in schizophrenia.
        Biol Psychiatry. 2011; 69: 180-187
        • Kim A.H.
        • Reimers M.
        • Maher B.
        • Williamson V.
        • McMichael O.
        • McClay J.L.
        • et al.
        MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders.
        Schizophr Res. 2010; 124: 183-191
        • Remenyi J.
        • van den Bosch M.W.
        • Palygin O.
        • Mistry R.B.
        • McKenzie C.
        • Macdonald A.
        • et al.
        miR-132/212 knockout mice reveal roles for these miRNAs in regulating cortical synaptic transmission and plasticity.
        PloS One. 2013; 8: e62509
        • Wang R.Y.
        • Phang R.Z.
        • Hsu P.H.
        • Wang W.H.
        • Huang H.T.
        • Liu I.Y.
        In vivo knockdown of hippocampal miR-132 expression impairs memory acquisition of trace fear conditioning.
        Hippocampus. 2013; 23: 625-633
        • Gardiner E.
        • Beveridge N.J.
        • Wu J.Q.
        • Carr V.
        • Scott R.J.
        • Tooney P.A.
        • et al.
        Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells.
        Mol Psychiatry. 2012; 17: 827-840
        • Royo H.
        • Cavaille J.
        Non-coding RNAs in imprinted gene clusters.
        Biol Cell. 2008; 100: 149-166
        • Fiore R.
        • Khudayberdiev S.
        • Christensen M.
        • Siegel G.
        • Flavell S.W.
        • Kim T.K.
        • et al.
        Mef2-mediated transcription of the miR379-410 cluster regulates activity-dependent dendritogenesis by fine-tuning Pumilio2 protein levels.
        EMBO J. 2009; 28: 697-710
        • Lai C.Y.
        • Yu S.L.
        • Hsieh M.H.
        • Chen C.H.
        • Chen H.Y.
        • Wen C.C.
        • et al.
        MicroRNA expression aberration as potential peripheral blood biomarkers for schizophrenia.
        PloS One. 2011; 6: e21635
        • Shi W.
        • Du J.
        • Qi Y.
        • Liang G.
        • Wang T.
        • Li S.
        • et al.
        Aberrant expression of serum miRNAs in schizophrenia.
        J Psychiatr Res. 2012; 46: 198-204
        • Ripke S.
        • Sanders A.
        • Kendler K.
        • Levinson D.
        • Sklar P.
        • Holmans P.
        • et al.
        Genome-wide association study identifies five new schizophrenia loci.
        Nat Genet. 2011; 43: 969-976
        • Ripke S.
        • Neale B.M.
        • Corvin A.
        • Walters J.T.R.
        • Farh K.-H.
        • Holmans P.A.
        • et al.
        Biological insights from 108 schizophrenia-associated genetic loci.
        Nature. 2014; 511: 421-427
        • Sun G.
        • Ye P.
        • Murai K.
        • Lang M.F.
        • Li S.
        • Zhang H.
        • et al.
        miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells.
        Nat Commun. 2011; 2: 529
        • Wright C.
        • Turner J.A.
        • Calhoun V.D.
        • Perrone-Bizzozero N.
        Potential impact of miR-137 and its targets in schizophrenia.
        Front Genet. 2013; 4: 58
        • Guella I.
        • Sequeira A.
        • Rollins B.
        • Morgan L.
        • Torri F.
        • van Erp T.G.
        • et al.
        Analysis of miR-137 expression and rs1625579 in dorsolateral prefrontal cortex.
        J Psychiatr Res. 2013; 47: 1215-1221
        • van Erp T.G.
        • Guella I.
        • Vawter M.P.
        • Turner J.
        • Brown G.G.
        • McCarthy G.
        • et al.
        Schizophrenia miR-137 locus risk genotype is associated with dorsolateral prefrontal cortex hyperactivation.
        Biol Psychiatry. 2014; 75: 398-405
        • Begemann M.
        • Grube S.
        • Papiol S.
        • Malzahn D.
        • Krampe H.
        • Ribbe K.
        • et al.
        Modification of cognitive performance in schizophrenia by complexin 2 gene polymorphisms.
        Arch Gen Psychiatry. 2010; 67: 879-888
        • Maynard T.M.
        • Sikich L.
        • Lieberman J.A.
        • LaMantia A.S.
        Neural development, cell-cell signaling, and the “two-hit” hypothesis of schizophrenia.
        Schizophr Bull. 2001; 27: 457-476
        • Hollins S.L.
        • Zavitsanou K.
        • Walker F.R.
        • Cairns M.J.
        Alteration of imprinted Dlk1-Dio3 miRNA cluster expression in the entorhinal cortex induced by maternal immune activation and adolescent cannabinoid exposure.
        Transl Psychiatry. 2014; 4: e452
        • Samuels I.S.
        • Karlo J.C.
        • Faruzzi A.N.
        • Pickering K.
        • Herrup K.
        • Sweatt J.D.
        • et al.
        Deletion of ERK2 mitogen-activated protein kinase identifies its key roles in cortical neurogenesis and cognitive function.
        J Neurosci. 2008; 28: 6983-6995
        • Miyaoka T.
        • Seno H.
        • Ishino H.
        Increased expression of Wnt-1 in schizophrenic brains.
        Schizophr Res. 1999; 38: 1-6
        • Moreau M.P.
        • Bruse S.E.
        • David-Rus R.
        • Buyske S.
        • Brzustowicz L.M.
        Altered microRNA expression profiles in postmortem brain samples from individuals with schizophrenia and bipolar disorder.
        Biol Psychiatry. 2011; 69: 188-193
        • Miller B.H.
        • Zeier Z.
        • Xi L.
        • Lanz T.A.
        • Deng S.
        • Strathmann J.
        • et al.
        MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function.
        Proc Natl Acad Sci U S A. 2012; 109: 3125-3130
        • Smalheiser N.R.
        • Lugli G.
        • Zhang H.
        • Rizavi H.
        • Cook E.H.
        • Dwivedi Y.
        Expression of microRNAs and other small RNAs in prefrontal cortex in schizophrenia, bipolar disorder and depressed subjects.
        PloS One. 2014; 9: e86469
        • Banigan M.G.
        • Kao P.F.
        • Kozubek J.A.
        • Winslow A.R.
        • Medina J.
        • Costa J.
        • et al.
        Differential expression of exosomal microRNAs in prefrontal cortices of schizophrenia and bipolar disorder patients.
        PloS One. 2013; 8: e48814
        • Whalley H.C.
        • Papmeyer M.
        • Romaniuk L.
        • Sprooten E.
        • Johnstone E.C.
        • Hall J.
        • et al.
        Impact of a microRNA MIR137 susceptibility variant on brain function in people at high genetic risk of schizophrenia or bipolar disorder.
        Neuropsychopharmacology. 2012; 37: 2720-2729
        • Zhang Z.
        • Convertini P.
        • Shen M.
        • Xu X.
        • Lemoine F.
        • de la Grange P.
        • et al.
        Valproic acid causes proteasomal degradation of DICER and influences miRNA expression.
        PloS One. 2013; 8: e82895
        • Etain B.
        • Jamain S.
        • Milhiet V.
        • Lajnef M.
        • Boudebesse C.
        • Dumaine A.
        • et al.
        Association between circadian genes, bipolar disorders and chronotypes.
        Chronobiol Int. 2014; 31: 807-814
        • Rahman O.A.
        • Sasvari-Szekely M.
        • Szekely A.
        • Faludi G.
        • Guttman A.
        • Nemoda Z.
        Analysis of a polymorphic microRNA target site in the purinergic receptor P2RX7 gene.
        Electrophoresis. 2010; 31: 1790-1795
        • Sperlagh B.
        • Vizi E.S.
        • Wirkner K.
        • Illes P.
        P2X7 receptors in the nervous system.
        Prog Neurobiol. 2006; 78: 327-346
        • Xu Y.
        • Liu H.
        • Li F.
        • Sun N.
        • Ren Y.
        • Liu Z.
        • et al.
        A polymorphism in the microRNA-30e precursor associated with major depressive disorder risk and P300 waveform.
        J Affect Disord. 2010; 127: 332-336
        • He Y.
        • Zhou Y.
        • Xi Q.
        • Cui H.
        • Luo T.
        • Song H.
        • et al.
        Genetic variations in microRNA processing genes are associated with susceptibility in depression.
        DNA Cell Biol. 2012; 31: 1499-1506
        • Smalheiser N.R.
        • Lugli G.
        • Rizavi H.S.
        • Torvik V.I.
        • Turecki G.
        • Dwivedi Y.
        MicroRNA expression is down-regulated and reorganized in prefrontal cortex of depressed suicide subjects.
        PloS One. 2012; 7: e33201
        • Smalheiser N.R.
        • Lugli G.
        • Rizavi H.S.
        • Zhang H.
        • Torvik V.I.
        • Pandey G.N.
        • et al.
        MicroRNA expression in rat brain exposed to repeated inescapable shock: Differential alterations in learned helplessness vs. non-learned helplessness.
        Int J Neuropsychopharmacol. 2011; 14: 1315-1325
        • Xu S.
        • Witmer P.D.
        • Lumayag S.
        • Kovacs B.
        • Valle D.
        MicroRNA (miRNA) transcriptome of mouse retina and identification of a sensory organ-specific miRNA cluster.
        J Biol Chem. 2007; 282: 25053-25066
        • Mendlewicz J.
        Disruption of the circadian timing systems: Molecular mechanisms in mood disorders.
        CNS Drugs. 2009; 23: 15-26
        • Li Y.J.
        • Xu M.
        • Gao Z.H.
        • Wang Y.Q.
        • Yue Z.
        • Zhang Y.X.
        • et al.
        Alterations of serum levels of BDNF-related miRNAs in patients with depression.
        PloS One. 2013; 8: e63648
        • Zheng Z.
        • Zeng Y.
        • Huang H.
        • Xu F.
        MicroRNA-132 may play a role in coexistence of depression and cardiovascular disease: A hypothesis.
        Med Sci Monit. 2013; 19: 438-443
        • Cheng H.Y.
        • Papp J.W.
        • Varlamova O.
        • Dziema H.
        • Russell B.
        • Curfman J.P.
        • et al.
        microRNA modulation of circadian-clock period and entrainment.
        Neuron. 2007; 54: 813-829
        • Abu-Elneel K.
        • Liu T.
        • Gazzaniga F.S.
        • Nishimura Y.
        • Wall D.P.
        • Geschwind D.H.
        • et al.
        Heterogeneous dysregulation of microRNAs across the autism spectrum.
        Neurogenetics. 2008; 9: 153-161
        • Buyske S.
        Comment on the article “Heterogeneous dysregulation of microRNAs across the autism spectrum” by Abu-Elneel et al.
        Neurogenetics. 2009; 10 (author reply 169–170): 167
        • Talebizadeh Z.
        • Butler M.G.
        • Theodoro M.F.
        Feasibility and relevance of examining lymphoblastoid cell lines to study role of microRNAs in autism.
        Autism Res. 2008; 1: 240-250
        • Sarachana T.
        • Zhou R.
        • Chen G.
        • Manji H.K.
        • Hu V.W.
        Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines.
        Genome Med. 2010; 2: 23
        • Ghahramani Seno M.M.
        • Hu P.
        • Gwadry F.G.
        • Pinto D.
        • Marshall C.R.
        • Casallo G.
        • et al.
        Gene and miRNA expression profiles in autism spectrum disorders.
        Brain Res. 2011; 1380: 85-97
        • Hemmat M.
        • Rumple M.J.
        • Mahon L.W.
        • Strom C.M.
        • Anguiano A.
        • Talai M.
        • et al.
        Short stature, digit anomalies and dysmorphic facial features are associated with the duplication of miR-17 ~ 92 cluster.
        Mol Cytogenet. 2014; 7: 27
        • Kannu P.
        • Campos-Xavier A.B.
        • Hull D.
        • Martinet D.
        • Ballhausen D.
        • Bonafe L.
        Post-axial polydactyly type A2, overgrowth and autistic traits associated with a chromosome 13q31.3 microduplication encompassing miR-17-92 and GPC5.
        Eur J Med Genet. 2013; 56: 452-457
        • Miller D.T.
        • Shen Y.
        • Weiss L.A.
        • Korn J.
        • Anselm I.
        • Bridgemohan C.
        • et al.
        Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders.
        J Med Genet. 2009; 46: 242-248
        • Vaishnavi V.
        • Manikandan M.
        • Tiwary B.K.
        • Munirajan A.K.
        Insights on the functional impact of microRNAs present in autism-associated copy number variants.
        PloS One. 2013; 8: e56781
        • Marrale M.
        • Albanese N.N.
        • Cali F.
        • Romano V.
        Assessing the impact of copy number variants on miRNA genes in autism by Monte Carlo simulation.
        PloS One. 2014; 9: e90947
        • Davis M.E.
        • Zuckerman J.E.
        • Choi C.H.
        • Seligson D.
        • Tolcher A.
        • Alabi C.A.
        • et al.
        Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles.
        Nature. 2010; 464: 1067-1070
        • Hullinger T.G.
        • Montgomery R.L.
        • Seto A.G.
        • Dickinson B.A.
        • Semus H.M.
        • Lynch J.M.
        • et al.
        Inhibition of miR-15 protects against cardiac ischemic injury.
        Circ Res. 2012; 110: 71-81
        • Krutzfeldt J.
        • Kuwajima S.
        • Braich R.
        • Rajeev K.G.
        • Pena J.
        • Tuschl T.
        • et al.
        Specificity, duplex degradation and subcellular localization of antagomirs.
        Nucleic Acids Res. 2007; 35: 2885-2892
        • Ouyang Y.B.
        • Lu Y.
        • Yue S.
        • Xu L.J.
        • Xiong X.X.
        • White R.E.
        • et al.
        miR-181 regulates GRP78 and influences outcome from cerebral ischemia in vitro and in vivo.
        Neurobiol Dis. 2012; 45: 555-563
        • Yin K.J.
        • Deng Z.
        • Huang H.
        • Hamblin M.
        • Xie C.
        • Zhang J.
        • et al.
        miR-497 regulates neuronal death in mouse brain after transient focal cerebral ischemia.
        Neurobiol Dis. 2010; 38: 17-26
        • Ziats M.N.
        • Rennert O.M.
        Identification of differentially expressed microRNAs across the developing human brain.
        Mol Psychiatry. 2014; 19: 848-852
        • Beveridge N.J.
        • Santarelli D.M.
        • Wang X.
        • Tooney P.A.
        • Webster M.J.
        • Weickert C.S.
        • et al.
        Maturation of the human dorsolateral prefrontal cortex coincides with a dynamic shift in microRNA expression.
        Schizophr Bull. 2014; 40: 399-409
        • Hollins S.L.
        • Goldie B.J.
        • Carroll A.P.
        • Mason E.A.
        • Walker F.R.
        • Eyles D.W.
        • et al.
        Ontogeny of small RNA in the regulation of mammalian brain development.
        BMC Genom. 2014; 15: 777
        • Sasaki Y.
        • Gross C.
        • Xing L.
        • Goshima Y.
        • Bassell G.J.
        Identification of axon-enriched microRNAs localized to growth cones of cortical neurons.
        Dev Neurobiol. 2014; 74: 397-406
        • Barbato C.
        • Ciotti M.T.
        • Serafino A.
        • Calissano P.
        • Cogoni C.
        Dicer expression and localization in post-mitotic neurons.
        Brain Res. 2007; 1175: 17-27
        • Green M.J.
        • Cairns M.J.
        • Wu J.
        • Dragovic M.
        • Jablensky A.
        • Tooney P.A.
        • et al.
        Genome-wide supported variant MIR137 and severe negative symptoms predict membership of an impaired cognitive subtype of schizophrenia.
        Mol Psychiatry. 2013; 18: 774-780
        • Wong J.
        • Duncan C.E.
        • Beveridge N.J.
        • Webster M.J.
        • Cairns M.J.
        • Weickert C.S.
        Expression of NPAS3 in the human cortex and evidence of its posttranscriptional regulation by miR-17 during development, with implications for schizophrenia.
        Schizophr Bull. 2013; 39: 396-406
        • Xu Y.
        • Li F.
        • Zhang B.
        • Zhang K.
        • Zhang F.
        • Huang X.
        • et al.
        MicroRNAs and target site screening reveals a pre-microRNA-30e variant associated with schizophrenia.
        Schizophr Res. 2010; 119: 219-227
        • Mellios N.
        • Galdzicka M.
        • Ginns E.
        • Baker S.P.
        • Rogaev E.
        • Xu J.
        • et al.
        Gender-specific reduction of estrogen-sensitive small RNA, miR-30b, in subjects with schizophrenia.
        Schizophr Bull. 2012; 38: 433-443
        • Tabares-Seisdedos R.
        • Rubenstein J.L.
        Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: Implications for schizophrenia, autism and cancer.
        Mol Psychiatry. 2009; 14: 563-589
        • Shih W.L.
        • Kao C.F.
        • Chuang L.C.
        • Kuo P.H.
        Incorporating information of microRNAs into pathway analysis in a genome-wide association study of bipolar disorder.
        Front Genet. 2012; 3: 293
        • Belzeaux R.
        • Bergon A.
        • Jeanjean V.
        • Loriod B.
        • Formisano-Treziny C.
        • Verrier L.
        • et al.
        Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode.
        Transl Psychiatry. 2012; 2: e185
        • Cao M.Q.
        • Chen D.H.
        • Zhang C.H.
        • Wu Z.Z.
        Screening of specific microRNA in hippocampus of depression model rats and intervention effect of Chaihu Shugan San [in Chinese].
        Zhongguo Zhong Yao Za Zhi. 2013; 38: 1585-1589