Advertisement

Inhibition of 14-3-3 Proteins Leads to Schizophrenia-Related Behavioral Phenotypes and Synaptic Defects in Mice

Published:February 19, 2015DOI:https://doi.org/10.1016/j.biopsych.2015.02.015

      Abstract

      Background

      The 14-3-3 family of proteins is implicated in the regulation of several key neuronal processes. Previous human and animal studies suggested an association between 14-3-3 dysregulation and schizophrenia.

      Methods

      We characterized behavioral and functional changes in transgenic mice that express an isoform-independent 14-3-3 inhibitor peptide in the brain.

      Results

      We recently showed that 14-3-3 functional knockout mice (FKO) exhibit impairments in associative learning and memory. We report here that these 14-3-3 FKO mice display other behavioral deficits that correspond to the core symptoms of schizophrenia. These behavioral deficits may be attributed to alterations in multiple neurotransmission systems in the 14-3-3 FKO mice. In particular, inhibition of 14-3-3 proteins results in a reduction of dendritic complexity and spine density in forebrain excitatory neurons, which may underlie the altered synaptic connectivity in the prefrontal cortical synapse of the 14-3-3 FKO mice. At the molecular level, this dendritic spine defect may stem from dysregulated actin dynamics secondary to a disruption of the 14-3-3-dependent regulation of phosphorylated cofilin.

      Conclusions

      Collectively, our data provide a link between 14-3-3 dysfunction, synaptic alterations, and schizophrenia-associated behavioral deficits.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • van Os J.
        • Kapur S.
        Schizophrenia.
        Lancet. 2009; 374: 635-645
        • Ikeda M.
        • Hikita T.
        • Taya S.
        • Uraguchi-Asaki J.
        • Toyo-oka K.
        • Wynshaw-Boris A.
        • et al.
        Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia.
        Hum Mol Genet. 2008; 17: 3212-3222
        • Jia Y.
        • Yu X.
        • Zhang B.
        • Yuan Y.
        • Xu Q.
        • Shen Y.
        An association study between polymorphisms in three genes of 14-3-3 (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein) family and paranoid schizophrenia in northern Chinese population.
        Eur Psychiatry. 2004; 19: 377-379
        • Wong A.H.
        • Likhodi O.
        • Trakalo J.
        • Yusuf M.
        • Sinha A.
        • Pato C.N.
        • et al.
        Genetic and post-mortem mRNA analysis of the 14-3-3 genes that encode phosphoserine/threonine-binding regulatory proteins in schizophrenia and bipolar disorder.
        Schizophr Res. 2005; 78: 137-146
        • Bell R.
        • Munro J.
        • Russ C.
        • Powell J.F.
        • Bruinvels A.
        • Kerwin R.W.
        • et al.
        Systematic screening of the 14-3-3 eta (eta) chain gene for polymorphic variants and case-control analysis in schizophrenia.
        Am J Med Genet. 2000; 96: 736-743
        • Toyooka K.
        • Muratake T.
        • Tanaka T.
        • Igarashi S.
        • Watanabe H.
        • Takeuchi H.
        • et al.
        14-3-3 protein eta chain gene (YWHAH) polymorphism and its genetic association with schizophrenia.
        Am J Med Genet. 1999; 88: 164-167
        • Muratake T.
        • Hayashi S.
        • Ichikawa T.
        • Kumanishi T.
        • Ichimura Y.
        • Kuwano R.
        • et al.
        Structural organization and chromosomal assignment of the human 14-3-3 eta chain gene (YWHAH).
        Genomics. 1996; 36: 63-69
        • Middleton F.A.
        • Peng L.
        • Lewis D.A.
        • Levitt P.
        • Mirnics K.
        Altered expression of 14-3-3 genes in the prefrontal cortex of subjects with schizophrenia.
        Neuropsychopharmacology. 2005; 30: 974-983
        • Vawter M.P.
        • Barrett T.
        • Cheadle C.
        • Sokolov B.P.
        • Wood 3rd, W.H.
        • Donovan D.M.
        • et al.
        Application of cDNA microarrays to examine gene expression differences in schizophrenia.
        Brain Res Bull. 2001; 55: 641-650
        • Qiao H.
        • Foote M.
        • Graham K.
        • Wu Y.
        • Zhou Y.
        14-3-3 proteins are required for hippocampal long-term potentiation and associative learning and memory.
        J Neurosci. 2014; 34: 4801-4808
        • Kirov G.
        • Pocklington A.J.
        • Holmans P.
        • Ivanov D.
        • Ikeda M.
        • Ruderfer D.
        • et al.
        De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia.
        Mol Psychiatry. 2012; 17: 142-153
        • Fromer M.
        • Pocklington A.J.
        • Kavanagh D.H.
        • Williams H.J.
        • Dwyer S.
        • Gormley P.
        • et al.
        De novo mutations in schizophrenia implicate synaptic networks.
        Nature. 2014; 506: 179-184
        • Berg D.
        • Holzmann C.
        • Riess O.
        14-3-3 proteins in the nervous system.
        Nat Rev Neurosci. 2003; 4: 752-762
        • Liu D.
        • Bienkowska J.
        • Petosa C.
        • Collier R.J.
        • Fu H.
        • Liddington R.
        Crystal structure of the zeta isoform of the 14-3-3 protein.
        Nature. 1995; 376: 191-194
        • Rittinger K.
        • Budman J.
        • Xu J.
        • Volinia S.
        • Cantley L.C.
        • Smerdon S.J.
        • et al.
        Structural analysis of 14-3-3 phosphopeptide complexes identifies a dual role for the nuclear export signal of 14-3-3 in ligand binding.
        Mol Cell. 1999; 4: 153-166
        • Martin H.
        • Rostas J.
        • Patel Y.
        • Aitken A.
        Subcellular localisation of 14-3-3 isoforms in rat brain using specific antibodies.
        J Neurochem. 1994; 63: 2259-2265
        • Baxter H.C.
        • Liu W.G.
        • Forster J.L.
        • Aitken A.
        • Fraser J.R.
        Immunolocalisation of 14-3-3 isoforms in normal and scrapie-infected murine brain.
        Neuroscience. 2002; 109: 5-14
        • Broadie K.
        • Rushton E.
        • Skoulakis E.M.
        • Davis R.L.
        Leonardo, a Drosophila 14-3-3 protein involved in learning, regulates presynaptic function.
        Neuron. 1997; 19: 391-402
        • Li Y.
        • Wu Y.
        • Zhou Y.
        Modulation of inactivation properties of CaV2.2 channels by 14-3-3 proteins.
        Neuron. 2006; 51: 755-771
        • Zhou Y.
        • Schopperle W.M.
        • Murrey H.
        • Jaramillo A.
        • Dagan D.
        • Griffith L.C.
        • et al.
        A dynamically regulated 14-3-3, Slob, and Slowpoke potassium channel complex in Drosophila presynaptic nerve terminals.
        Neuron. 1999; 22: 809-818
        • Fu H.
        • Subramanian R.R.
        • Masters S.C.
        14-3-3 proteins: Structure, function, and regulation.
        Annu Rev Pharmacol Toxicol. 2000; 40: 617-647
        • Skoulakis E.M.
        • Davis R.L.
        Olfactory learning deficits in mutants for leonardo, a Drosophila gene encoding a 14-3-3 protein.
        Neuron. 1996; 17: 931-944
        • Roncada P.
        • Bortolato M.
        • Frau R.
        • Saba P.
        • Flore G.
        • Soggiu A.
        • et al.
        Gating deficits in isolation-reared rats are correlated with alterations in protein expression in nucleus accumbens.
        J Neurochem. 2009; 108: 611-620
        • Taya S.
        • Shinoda T.
        • Tsuboi D.
        • Asaki J.
        • Nagai K.
        • Hikita T.
        • et al.
        DISC1 regulates the transport of the NUDEL/LIS1/14-3-3epsilon complex through kinesin-1.
        J Neurosci. 2007; 27: 15-26
        • Skoulakis E.M.
        • Davis R.L.
        14-3-3 proteins in neuronal development and function.
        Mol Neurobiol. 1998; 16: 269-284
        • Yam P.T.
        • Kent C.B.
        • Morin S.
        • Farmer W.T.
        • Alchini R.
        • Lepelletier L.
        • et al.
        14-3-3 proteins regulate a cell-intrinsic switch from sonic hedgehog-mediated commissural axon attraction to repulsion after midline crossing.
        Neuron. 2012; 76: 735-749
        • Yacoubian T.A.
        • Slone S.R.
        • Harrington A.J.
        • Hamamichi S.
        • Schieltz J.M.
        • Caldwell K.A.
        • et al.
        Differential neuroprotective effects of 14-3-3 proteins in models of Parkinsonʼs disease.
        Cell Death Dis. 2010; 1: e2
        • Toyo-oka K.
        • Shionoya A.
        • Gambello M.J.
        • Cardoso C.
        • Leventer R.
        • Ward H.L.
        • et al.
        14-3-3epsilon is important for neuronal migration by binding to NUDEL: A molecular explanation for Miller-Dieker syndrome.
        Nat Genet. 2003; 34: 274-285
        • Cheah P.S.
        • Ramshaw H.S.
        • Thomas P.Q.
        • Toyo-Oka K.
        • Xu X.
        • Martin S.
        • et al.
        Neurodevelopmental and neuropsychiatric behaviour defects arise from 14-3-3zeta deficiency.
        Mol Psychiatry. 2012; 17: 451-466
        • Masters S.C.
        • Fu H.
        14-3-3 proteins mediate an essential anti-apoptotic signal.
        J Biol Chem. 2001; 276: 45193-45200
        • Nestler E.J.
        • Hyman S.E.
        Animal models of neuropsychiatric disorders.
        Nat Neurosci. 2010; 13: 1161-1169
        • Koyama Y.
        • Hattori T.
        • Shimizu S.
        • Taniguchi M.
        • Yamada K.
        • Takamura H.
        • et al.
        DBZ (DISC1-binding zinc finger protein)-deficient mice display abnormalities in basket cells in the somatosensory cortices.
        J Chem Neuroanat. 2013; 53: 1-10
        • Sholl D.A.
        Dendritic organization in the neurons of the visual and motor cortices of the cat.
        J Anat. 1953; 87: 387-406
        • Verret L.
        • Mann E.O.
        • Hang G.B.
        • Barth A.M.
        • Cobos I.
        • Ho K.
        • et al.
        Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model.
        Cell. 2012; 149: 708-721
        • Li Y.C.
        • Kellendonk C.
        • Simpson E.H.
        • Kandel E.R.
        • Gao W.J.
        D2 receptor overexpression in the striatum leads to a deficit in inhibitory transmission and dopamine sensitivity in mouse prefrontal cortex.
        Proc Natl Acad Sci U S A. 2011; 108: 12107-12112
        • Hallett P.J.
        • Collins T.L.
        • Standaert D.G.
        • Dunah A.W.
        Biochemical fractionation of brain tissue for studies of receptor distribution and trafficking. Curr Protoc Neurosci Chapter 1.
        Unit. 2008; 1: 16
        • Wang B.
        • Yang H.
        • Liu Y.C.
        • Jelinek T.
        • Zhang L.
        • Ruoslahti E.
        • et al.
        Isolation of high-affinity peptide antagonists of 14-3-3 proteins by phage display.
        Biochemistry. 1999; 38: 12499-12504
        • Caroni P.
        Overexpression of growth-associated proteins in the neurons of adult transgenic mice.
        J Neurosci Methods. 1997; 71: 3-9
        • Feng G.
        • Mellor R.H.
        • Bernstein M.
        • Keller-Peck C.
        • Nguyen Q.T.
        • Wallace M.
        • et al.
        Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP.
        Neuron. 2000; 28: 41-51
        • Deutsch S.I.
        • Hitri A.
        Measurement of an explosive behavior in the mouse, induced by MK-801, a PCP analogue.
        Clin Neuropharmacol. 1993; 16: 251-257
        • Park S.
        • Holzman P.S.
        Schizophrenics show spatial working memory deficits.
        Arch Gen Psychiatry. 1992; 49: 975-982
        • Deacon R.M.
        • Rawlins J.N.
        T-maze alternation in the rodent.
        Nat Protoc. 2006; 1: 7-12
        • Powell S.B.
        • Weber M.
        • Geyer M.A.
        Genetic models of sensorimotor gating: Relevance to neuropsychiatric disorders.
        Curr Top Behav Neurosci. 2012; 12: 251-318
        • Moy S.S.
        • Nadler J.J.
        • Perez A.
        • Barbaro R.P.
        • Johns J.M.
        • Magnuson T.R.
        • et al.
        Sociability and preference for social novelty in five inbred strains: An approach to assess autistic-like behavior in mice.
        Genes Brain Behav. 2004; 3: 287-302
        • Howes O.D.
        • Kapur S.
        The dopamine hypothesis of schizophrenia: Version III—the final common pathway.
        Schizophr Bull. 2009; 35: 549-562
        • Ramshaw H.
        • Xu X.
        • Jaehne E.J.
        • McCarthy P.
        • Greenberg Z.
        • Saleh E.
        • et al.
        Locomotor hyperactivity in 14-3-3zeta KO mice is associated with dopamine transporter dysfunction.
        Transl Psychiatry. 2013; 3: e327
        • Kehrer C.
        • Maziashvili N.
        • Dugladze T.
        • Gloveli T.
        Altered excitatory-inhibitory balance in the NMDA-hypofunction model of schizophrenia.
        Front Mol Neurosci. 2008; 1: 6
        • Volk D.W.
        • Lewis D.A.
        Prefrontal cortical circuits in schizophrenia.
        Curr Top Behav Neurosci. 2010; 4: 485-508
        • Kulkarni V.A.
        • Firestein B.L.
        The dendritic tree and brain disorders.
        Mol Cell Neurosci. 2012; 50: 10-20
        • Penzes P.
        • Cahill M.E.
        • Jones K.A.
        • VanLeeuwen J.E.
        • Woolfrey K.M.
        Dendritic spine pathology in neuropsychiatric disorders.
        Nat Neurosci. 2011; 14: 285-293
        • Gohla A.
        • Bokoch G.M.
        14-3-3 regulates actin dynamics by stabilizing phosphorylated cofilin.
        Curr Biol. 2002; 12: 1704-1710
        • Soosairajah J.
        • Maiti S.
        • Wiggan O.
        • Sarmiere P.
        • Moussi N.
        • Sarcevic B.
        • et al.
        Interplay between components of a novel LIM kinase-slingshot phosphatase complex regulates cofilin.
        EMBO J. 2005; 24: 473-486
        • Toyo-Oka K.
        • Wachi T.
        • Hunt R.F.
        • Baraban S.C.
        • Taya S.
        • Ramshaw H.
        • et al.
        14-3-3epsilon and zeta regulate neurogenesis and differentiation of neuronal progenitor cells in the developing brain.
        J Neurosci. 2014; 34: 12168-12181
        • Keshavan M.S.
        • Tandon R.
        • Boutros N.N.
        • Nasrallah H.A.
        Schizophrenia, “just the facts”: What we know in 2008. Part 3: Neurobiology.
        Schizophr Res. 2008; 106: 89-107
        • Wang J.
        • Lou H.
        • Pedersen C.J.
        • Smith A.D.
        • Perez R.G.
        14-3-3zeta contributes to tyrosine hydroxylase activity in MN9D cells: Localization of dopamine regulatory proteins to mitochondria.
        J Biol Chem. 2009; 284: 14011-14019
        • Lodge D.J.
        • Grace A.A.
        Hippocampal dysfunction and disruption of dopamine system regulation in an animal model of schizophrenia.
        Neurotox Res. 2008; 14: 97-104
        • Lodge D.J.
        • Grace A.A.
        Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia.
        Trends Pharmacol Sci. 2011; 32: 507-513
        • Turrigiano G.G.
        • Nelson S.B.
        Homeostatic plasticity in the developing nervous system.
        Nat Rev Neurosci. 2004; 5: 97-107
        • Glausier J.R.
        • Lewis D.A.
        Dendritic spine pathology in schizophrenia.
        Neuroscience. 2013; 251: 90-107
        • Kent C.B.
        • Shimada T.
        • Ferraro G.B.
        • Ritter B.
        • Yam P.T.
        • McPherson P.S.
        • et al.
        14-3-3 proteins regulate protein kinase a activity to modulate growth cone turning responses.
        J Neurosci. 2010; 30: 14059-14067
        • Koleske A.J.
        Molecular mechanisms of dendrite stability.
        Nat Rev Neurosci. 2013; 14: 536-550
        • Moghaddam B.
        • Javitt D.
        From revolution to evolution: The glutamate hypothesis of schizophrenia and its implication for treatment.
        Neuropsychopharmacology. 2012; 37: 4-15
        • Mohn A.R.
        • Gainetdinov R.R.
        • Caron M.G.
        • Koller B.H.
        Mice with reduced NMDA receptor expression display behaviors related to schizophrenia.
        Cell. 1999; 98: 427-436
        • Ramsey A.J.
        • Milenkovic M.
        • Oliveira A.F.
        • Escobedo-Lozoya Y.
        • Seshadri S.
        • Salahpour A.
        • et al.
        Impaired NMDA receptor transmission alters striatal synapses and DISC1 protein in an age-dependent manner.
        Proc Natl Acad Sci U S A. 2011; 108: 5795-5800
        • Sun J.
        • Jia P.
        • Fanous A.H.
        • van den Oord E.
        • Chen X.
        • Riley B.P.
        • et al.
        Schizophrenia gene networks and pathways and their applications for novel candidate gene selection.
        PLoS One. 2010; 5: e11351
        • Foote M.
        • Zhou Y.
        14-3-3 proteins in neurological disorders.
        Int J Biochem Mol Biol. 2012; 3: 152-164