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Excitation/Inhibition Imbalance in Animal Models of Autism Spectrum Disorders

  • Author Footnotes
    1 EL and JK contributed equally to this work.
    Eunee Lee
    Footnotes
    1 EL and JK contributed equally to this work.
    Affiliations
    Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, Korea
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  • Author Footnotes
    1 EL and JK contributed equally to this work.
    Jiseok Lee
    Footnotes
    1 EL and JK contributed equally to this work.
    Affiliations
    Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea
    Search for articles by this author
  • Eunjoon Kim
    Correspondence
    Address correspondence to Eunjoon Kim, Ph.D., Korea Advanced Institute of Science and Technology, Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Yuseong-ku, Daejeon 34141, Republic of Korea.
    Affiliations
    Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, Korea

    Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea
    Search for articles by this author
  • Author Footnotes
    1 EL and JK contributed equally to this work.
Open AccessPublished:May 20, 2016DOI:https://doi.org/10.1016/j.biopsych.2016.05.011

      Abstract

      Imbalances between excitation and inhibition in synaptic transmission and neural circuits have been implicated in autism spectrum disorders. Excitation and inhibition imbalances are frequently observed in animal models of autism spectrum disorders, and their correction normalizes key autistic-like phenotypes in these animals. These results suggest that excitation and inhibition imbalances may contribute to the development and maintenance of autism spectrum disorders and represent an important therapeutic target.

      Keywords

      A tight balance between excitation and inhibition (E/I balance) in synaptic inputs to a neuron and in neural circuits is important for normal brain development and function. Accordingly, disturbed E/I balances have been implicated in various brain disorders, including autism spectrum disorders (ASDs) (
      • Rubenstein J.L.
      • Merzenich M.M.
      Model of autism: Increased ratio of excitation/inhibition in key neural systems.
      ,
      • Gogolla N.
      • Leblanc J.J.
      • Quast K.B.
      • Sudhof T.C.
      • Fagiolini M.
      • Hensch T.K.
      Common circuit defect of excitatory-inhibitory balance in mouse models of autism.
      ,
      • Nelson S.B.
      • Valakh V.
      Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders.
      ,
      • Cellot G.
      • Cherubini E.
      GABAergic signaling as therapeutic target for autism spectrum disorders.
      ,
      • Bourgeron T.
      The possible interplay of synaptic and clock genes in autism spectrum disorders.
      ,
      • Sudhof T.C.
      Neuroligins and neurexins link synaptic function to cognitive disease.
      ). An early, illuminating review by Rubenstein and Merzenich (
      • Rubenstein J.L.
      • Merzenich M.M.
      Model of autism: Increased ratio of excitation/inhibition in key neural systems.
      ) suggested the hypothesis that an increased E/I ratio in sensory, mnemonic, social, and emotional systems can cause ASDs. Since that time, a large body of clinical and neurobiological data has accumulated to support and refine this hypothesis.
      ASDs represent neurodevelopmental disorders characterized by social deficits and repetitive behaviors and accompanying comorbidities, including intellectual disability, epilepsy, hyperactivity, and anxiety. ASDs are associated with heterogeneous genetic variations, and the number of ASD-associated genes has risen to approximately 800 (
      • Abrahams B.S.
      • Arking D.E.
      • Campbell D.B.
      • Mefford H.C.
      • Morrow E.M.
      • Weiss L.A.
      • et al.
      SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs).
      ). ASDs are now the subject of intense worldwide investigations that seek to identify key underlying mechanisms capable of accounting for a large portion of ASD-related genetic variations and thus can serve as important therapeutic targets.
      This review summarizes results from animal models of ASD showing altered E/I balances. E/I balance is established and tightly regulated by a large number of factors, making it difficult to differentiate primary changes from secondary alterations in model animals, as was recently noted (
      • Nelson S.B.
      • Valakh V.
      Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders.
      ). Therefore, the emphasis is on those models that demonstrate rescue of ASD phenotypes using pharmacologic or cell type–specific gene-rescue approaches, or those models that use conditional gene-ablation approaches. Though valuable, other studies, including some that do not strongly support a causal relationship between the observed E/I imbalances and autistic-like phenotypes, are unavoidably less highlighted.

      E/I Imbalance and Autistic-Like Behaviors

      Abnormal connectivity and neural integration (or temporal binding), manifesting as abnormal brain rhythms, have been suggested to underlie ASDs (
      • Rippon G.
      • Brock J.
      • Brown C.
      • Boucher J.
      Disordered connectivity in the autistic brain: Challenges for the “new psychophysiology.”.
      ). Recent optogenetic studies have demonstrated that gamma-aminobutyric acidergic (GABAergic) interneurons expressing the calcium-buffering protein parvalbumin (PV) drive gamma rhythms and promote cortical circuit performance and cognitive flexibility (
      • Sohal V.S.
      • Zhang F.
      • Yizhar O.
      • Deisseroth K.
      Parvalbumin neurons and gamma rhythms enhance cortical circuit performance.
      ,
      • Cardin J.A.
      • Carlen M.
      • Meletis K.
      • Knoblich U.
      • Zhang F.
      • Deisseroth K.
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      Driving fast-spiking cells induces gamma rhythm and controls sensory responses.
      ). Importantly, a recent study has demonstrated that optogenetic stimulation of pyramidal neurons in the medial prefrontal cortex in mice induces social deficits associated with enhanced gamma oscillations, whereas coactivation of PV and pyramidal neurons does not induce social deficits (
      • Yizhar O.
      • Fenno L.E.
      • Prigge M.
      • Schneider F.
      • Davidson T.J.
      • O’Shea D.J.
      • et al.
      Neocortical excitation/inhibition balance in information processing and social dysfunction.
      ). These results collectively suggest that an increased neocortical E/I ratio caused by malfunctions of PV-expressing interneurons induces excessive gamma oscillations and autistic-like behaviors.

      Factors Contributing to E/I Imbalance

      Neuronal E/I balance involves regulation at synaptic or circuit levels. Specific factors that contribute to synaptic E/I balance would include excitatory/inhibitory synapse development, synaptic transmission and plasticity, downstream signaling pathways, homeostatic synaptic plasticity, and intrinsic neuronal excitability (Table 1). At the circuit level, E/I balance involves local circuits such as the interplay between GABAergic interneurons and target pyramidal neurons, which would modulate long-range connections.
      Table 1Mechanisms Underlying E/I Imbalances in Animal Models of ASD
      E/I Imbalance MechanismsExamples of Animal Models of ASD
      Excitatory Synapse DevelopmentEif4ebp2 (
      • Gkogkas C.G.
      • Khoutorsky A.
      • Ran I.
      • Rampakakis E.
      • Nevarko T.
      • Weatherill D.B.
      • et al.
      Autism-related deficits via dysregulated eIF4E-dependent translational control.
      )
      AMPARsBTBR (
      • Silverman J.L.
      • Oliver C.F.
      • Karras M.N.
      • Gastrell P.T.
      • Crawley J.N.
      AMPAKINE enhancement of social interaction in the BTBR mouse model of autism.
      ), Emx1-Cre;Syngap1+/fl (
      • Ozkan E.D.
      • Creson T.K.
      • Kramar E.A.
      • Rojas C.
      • Seese R.R.
      • Babyan A.H.
      • et al.
      Reduced cognition in Syngap1 mutants is caused by isolated damage within developing forebrain excitatory neurons.
      ), Emx1-Cre;Syngap1+/lox-stop (
      • Ozkan E.D.
      • Creson T.K.
      • Kramar E.A.
      • Rojas C.
      • Seese R.R.
      • Babyan A.H.
      • et al.
      Reduced cognition in Syngap1 mutants is caused by isolated damage within developing forebrain excitatory neurons.
      ), Mecp2 (
      • Nelson E.D.
      • Kavalali E.T.
      • Monteggia L.M.
      MeCP2-dependent transcriptional repression regulates excitatory neurotransmission.
      ,
      • Dani V.S.
      • Chang Q.
      • Maffei A.
      • Turrigiano G.G.
      • Jaenisch R.
      • Nelson S.B.
      Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome.
      ), Mecp2Tg1 (
      • Chao H.T.
      • Zoghbi H.Y.
      • Rosenmund C.
      MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number.
      ), Shank3 duplication (
      • Han K.
      • Holder Jr, J.L.
      • Schaaf C.P.
      • Lu H.
      • Chen H.
      • Kang H.
      • et al.
      SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties.
      ), Shank3 (various exon deletions) (
      • Bozdagi O.
      • Tavassoli T.
      • Buxbaum J.D.
      Insulin-like growth factor-1 rescues synaptic and motor deficits in a mouse model of autism and developmental delay.
      ,
      • Ramsey M.M.
      • Adams M.M.
      • Ariwodola O.J.
      • Sonntag W.E.
      • Weiner J.L.
      Functional characterization of des-IGF-1 action at excitatory synapses in the CA1 region of rat hippocampus.
      ,
      • Peca J.
      • Feliciano C.
      • Ting J.T.
      • Wang W.
      • Wells M.F.
      • Venkatraman T.N.
      • et al.
      Shank3 mutant mice display autistic-like behaviours and striatal dysfunction.
      ,
      • Lee J.
      • Chung C.
      • Ha S.
      • Lee D.
      • Kim D.Y.
      • Kim H.
      • Kim E.
      Shank3-mutant mice lacking exon 9 show altered excitation/inhibition balance, enhanced rearing, and spatial memory deficit.
      ,
      • Speed H.E.
      • Kouser M.
      • Xuan Z.
      • Reimers J.M.
      • Ochoa C.F.
      • Gupta N.
      • et al.
      Autism-associated insertion mutation (InsG) of Shank3 exon 21 causes impaired synaptic transmission and behavioral deficits.
      ,
      • Kouser M.
      • Speed H.E.
      • Dewey C.M.
      • Reimers J.M.
      • Widman A.J.
      • Gupta N.
      • et al.
      Loss of predominant Shank3 isoforms results in hippocampus-dependent impairments in behavior and synaptic transmission.
      ), Tau-Mecp2 (
      • Na E.S.
      • Nelson E.D.
      • Adachi M.
      • Autry A.E.
      • Mahgoub M.A.
      • Kavalali E.T.
      • Monteggia L.M.
      A mouse model for MeCP2 duplication syndrome: MeCP2 overexpression impairs learning and memory and synaptic transmission.
      ), Syngap1+/– (
      • Clement J.P.
      • Aceti M.
      • Creson T.K.
      • Ozkan E.D.
      • Shi Y.
      • Reish N.J.
      • et al.
      Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses.
      ), Ube3a (
      • Baudry M.
      • Kramar E.
      • Xu X.
      • Zadran H.
      • Moreno S.
      • Lynch G.
      • et al.
      Ampakines promote spine actin polymerization, long-term potentiation, and learning in a mouse model of Angelman syndrome.
      )
      NMDARsBaiap2 (IRSp53) (
      • Chung W.
      • Choi S.Y.
      • Lee E.
      • Park H.
      • Kang J.
      • Park H.
      • et al.
      Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression.
      ), BALB/c (
      • Benson A.D.
      • Burket J.A.
      • Deutsch S.I.
      Balb/c mice treated with D-cycloserine arouse increased social interest in conspecifics.
      ,
      • Deutsch S.I.
      • Pepe G.J.
      • Burket J.A.
      • Winebarger E.E.
      • Herndon A.L.
      • Benson A.D.
      D-cycloserine improves sociability and spontaneous stereotypic behaviors in 4-week old mice.
      ), BTBR (
      • Burket J.A.
      • Benson A.D.
      • Tang A.H.
      • Deutsch S.I.
      D-Cycloserine improves sociability in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorders with altered Ras/Raf/ERK1/2 signaling.
      ), Grid1 (GluD1) (
      • Yadav R.
      • Hillman B.G.
      • Gupta S.C.
      • Suryavanshi P.
      • Bhatt J.M.
      • Pavuluri R.
      • et al.
      Deletion of glutamate delta-1 receptor in mouse leads to enhanced working memory and deficit in fear conditioning.
      ), Grin1 (GluN1) (
      • Gandal M.J.
      • Anderson R.L.
      • Billingslea E.N.
      • Carlson G.C.
      • Roberts T.P.
      • Siegel S.J.
      Mice with reduced NMDA receptor expression: More consistent with autism than schizophrenia?.
      ), Nlgn1 (
      • Blundell J.
      • Blaiss C.A.
      • Etherton M.R.
      • Espinosa F.
      • Tabuchi K.
      • Walz C.
      • et al.
      Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior.
      ), Rats with low prosocial USVs (
      • Burgdorf J.
      • Moskal J.R.
      • Brudzynski S.M.
      • Panksepp J.
      Rats selectively bred for low levels of play-induced 50 kHz vocalizations as a model for autism spectrum disorders: a role for NMDA receptors.
      ), Shank2 (exons 6–7) (
      • Won H.
      • Lee H.R.
      • Gee H.Y.
      • Mah W.
      • Kim J.I.
      • Lee J.
      • et al.
      Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function.
      ,
      • Lee E.J.
      • Lee H.
      • Huang T.N.
      • Chung C.
      • Shin W.
      • Kim K.
      • et al.
      Trans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation.
      ), Shank2 (exon 7) (
      • Schmeisser M.J.
      • Ey E.
      • Wegener S.
      • Bockmann J.
      • Stempel V.
      • Kuebler A.
      • et al.
      Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2.
      ), Shank3 (exons 4–9) (
      • Bozdagi O.
      • Sakurai T.
      • Papapetrou D.
      • Wang X.
      • Dickstein D.L.
      • Takahashi N.
      • et al.
      Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication.
      ), Shank3 (exon 21G) (
      • Speed H.E.
      • Kouser M.
      • Xuan Z.
      • Reimers J.M.
      • Ochoa C.F.
      • Gupta N.
      • et al.
      Autism-associated insertion mutation (InsG) of Shank3 exon 21 causes impaired synaptic transmission and behavioral deficits.
      ), Shank3+/ΔC (
      • Duffney L.J.
      • Zhong P.
      • Wei J.
      • Matas E.
      • Cheng J.
      • Qin L.
      • et al.
      Autism-like deficits in Shank3-deficient mice are rescued by targeting actin regulators.
      ), Tbr1+/– (
      • Lee E.J.
      • Lee H.
      • Huang T.N.
      • Chung C.
      • Shin W.
      • Kim K.
      • et al.
      Trans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation.
      ,
      • Huang T.N.
      • Chuang H.C.
      • Chou W.H.
      • Chen C.Y.
      • Wang H.F.
      • Chou S.J.
      • Hsueh Y.P.
      Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality.
      ), VPA rats and mice (
      • Rinaldi T.
      • Perrodin C.
      • Markram H.
      Hyper-connectivity and hyper-plasticity in the medial prefrontal cortex in the valproic Acid animal model of autism.
      ,
      • Rinaldi T.
      • Kulangara K.
      • Antoniello K.
      • Markram H.
      Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid.
      ,
      • Kim K.C.
      • Lee D.K.
      • Go H.S.
      • Kim P.
      • Choi C.S.
      • Kim J.W.
      • et al.
      Pax6-dependent cortical glutamatergic neuronal differentiation regulates autism-like behavior in prenatally valproic acid-exposed rat offspring.
      ,
      • Kang J.
      • Kim E.
      Suppression of NMDA receptor function in mice prenatally exposed to valproic acid improves social deficits and repetitive behaviors.
      )
      mGluRsBaiap2 (IRSp53) (
      • Chung W.
      • Choi S.Y.
      • Lee E.
      • Park H.
      • Kang J.
      • Park H.
      • et al.
      Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression.
      ), BTBR (
      • Silverman J.L.
      • Smith D.G.
      • Rizzo S.J.
      • Karras M.N.
      • Turner S.M.
      • Tolu S.S.
      • et al.
      Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism.
      ,
      • Silverman J.L.
      • Tolu S.S.
      • Barkan C.L.
      • Crawley J.N.
      Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP.
      ,
      • Seese R.R.
      • Maske A.R.
      • Lynch G.
      • Gall C.M.
      Long-term memory deficits are associated with elevated synaptic ERK1/2 activation and reversed by mGluR5 antagonism in an animal model of autism.
      ), Fmr1 (
      • Michalon A.
      • Bruns A.
      • Risterucci C.
      • Honer M.
      • Ballard T.M.
      • Ozmen L.
      • et al.
      Chronic metabotropic glutamate receptor 5 inhibition corrects local alterations of brain activity and improves cognitive performance in fragile X mice.
      ,
      • Michalon A.
      • Sidorov M.
      • Ballard T.M.
      • Ozmen L.
      • Spooren W.
      • Wettstein J.G.
      • et al.
      Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice.
      ,
      • Yuskaitis C.J.
      • Mines M.A.
      • King M.K.
      • Sweatt J.D.
      • Miller C.A.
      • Jope R.S.
      Lithium ameliorates altered glycogen synthase kinase-3 and behavior in a mouse model of fragile X syndrome.
      ,
      • Yan Q.J.
      • Rammal M.
      • Tranfaglia M.
      • Bauchwitz R.P.
      Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP.
      ,
      • Dolen G.
      • Osterweil E.
      • Rao B.S.
      • Smith G.B.
      • Auerbach B.D.
      • Chattarji S.
      • Bear M.F.
      Correction of fragile X syndrome in mice.
      ,
      • Auerbach B.D.
      • Osterweil E.K.
      • Bear M.F.
      Mutations causing syndromic autism define an axis of synaptic pathophysiology.
      ), Nlgn3 (
      • Baudouin S.J.
      • Gaudias J.
      • Gerharz S.
      • Hatstatt L.
      • Zhou K.
      • Punnakkal P.
      • et al.
      Shared synaptic pathophysiology in syndromic and nonsyndromic rodent models of autism.
      ), Shank2 (exons 6–7) (
      • Won H.
      • Lee H.R.
      • Gee H.Y.
      • Mah W.
      • Kim J.I.
      • Lee J.
      • et al.
      Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function.
      )
      Signaling PathwaysBTBR (
      • Amodeo D.A.
      • Jones J.H.
      • Sweeney J.A.
      • Ragozzino M.E.
      Risperidone and the 5-HT2A receptor antagonist M100907 improve probabilistic reversal learning in BTBR T + tf/J mice.
      ), Cntnap2 (
      • Penagarikano O.
      • Abrahams B.S.
      • Herman E.I.
      • Winden K.D.
      • Gdalyahu A.
      • Dong H.
      • et al.
      Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits.
      ), Emx1-Cre;Tsc1 (
      • Cambiaghi M.
      • Cursi M.
      • Magri L.
      • Castoldi V.
      • Comi G.
      • Minicucci F.
      • et al.
      Behavioural and EEG effects of chronic rapamycin treatment in a mouse model of tuberous sclerosis complex.
      ), Fmr1 (
      • Bhattacharya A.
      • Kaphzan H.
      • Alvarez-Dieppa A.C.
      • Murphy J.P.
      • Pierre P.
      • Klann E.
      Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice.
      ,
      • Dolan B.M.
      • Duron S.G.
      • Campbell D.A.
      • Vollrath B.
      • Shankaranarayana Rao B.S.
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      • et al.
      Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486.
      ,
      • Lim C.S.
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      • Stornetta R.L.
      • Scott M.M.
      • Zhu J.J.
      Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model.
      ), Nf1+/– (
      • Molosh A.I.
      • Johnson P.L.
      • Spence J.P.
      • Arendt D.
      • Federici L.M.
      • Bernabe C.
      • et al.
      Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase.
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      • et al.
      Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice.
      ), Pcp2/L7-Cre;Tsc1 (
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      • Greene-Colozzi E.
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      • et al.
      Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice.
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      • Shilyansky C.
      • Zhou Y.
      • Li W.
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      Reversal of learning deficits in a Tsc2+/– mouse model of tuberous sclerosis.
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      Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex.
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      Imbalanced mechanistic target of rapamycin C1 and C2 activity in the cerebellum of Angelman syndrome mice impairs motor function.
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      Autism-like deficits in Shank3-deficient mice are rescued by targeting actin regulators.
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      Inhibitory Synapse Development and FunctionD1-Cre;Nlgn3 (
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      Early developmental alterations in GABAergic protein expression in fragile X knockout mice.
      ,
      • Curia G.
      • Papouin T.
      • Seguela P.
      • Avoli M.
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      • et al.
      Mice lacking the beta3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome.
      ,
      • Homanics G.E.
      • DeLorey T.M.
      • Firestone L.L.
      • Quinlan J.J.
      • Handforth A.
      • Harrison N.L.
      • et al.
      Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior.
      ), Nlgn2 (
      • Liang J.
      • Xu W.
      • Hsu Y.T.
      • Yee A.X.
      • Chen L.
      • Sudhof T.C.
      Conditional neuroligin-2 knockout in adult medial prefrontal cortex links chronic changes in synaptic inhibition to cognitive impairments.
      ,
      • Poulopoulos A.
      • Aramuni G.
      • Meyer G.
      • Soykan T.
      • Hoon M.
      • Papadopoulos T.
      • et al.
      Neuroligin 2 drives postsynaptic assembly at perisomatic inhibitory synapses through gephyrin and collybistin.
      ), Nlgn3 (
      • Tabuchi K.
      • Blundell J.
      • Etherton M.R.
      • Hammer R.E.
      • Liu X.
      • Powell C.M.
      • Sudhof T.C.
      A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice.
      ,
      • Foldy C.
      • Malenka R.C.
      • Sudhof T.C.
      Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling.
      ,
      • Rothwell P.E.
      • Fuccillo M.V.
      • Maxeiner S.
      • Hayton S.J.
      • Gokce O.
      • Lim B.K.
      • et al.
      Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors.
      ), Nlgn3 R451C (
      • Tabuchi K.
      • Blundell J.
      • Etherton M.R.
      • Hammer R.E.
      • Liu X.
      • Powell C.M.
      • Sudhof T.C.
      A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice.
      ,
      • Foldy C.
      • Malenka R.C.
      • Sudhof T.C.
      Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling.
      ,
      • Rothwell P.E.
      • Fuccillo M.V.
      • Maxeiner S.
      • Hayton S.J.
      • Gokce O.
      • Lim B.K.
      • et al.
      Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors.
      ), Ube3a (
      • Egawa K.
      • Kitagawa K.
      • Inoue K.
      • Takayama M.
      • Takayama C.
      • Saitoh S.
      • et al.
      Decreased tonic inhibition in cerebellar granule cells causes motor dysfunction in a mouse model of Angelman syndrome.
      ,
      • Kaphzan H.
      • Hernandez P.
      • Jung J.I.
      • Cowansage K.K.
      • Deinhardt K.
      • Chao M.V.
      • et al.
      Reversal of impaired hippocampal long-term potentiation and contextual fear memory deficits in Angelman syndrome model mice by ErbB inhibitors.
      )
      InterneuronsBTBR (
      • Han S.
      • Tai C.
      • Jones C.J.
      • Scheuer T.
      • Catterall W.A.
      Enhancement of inhibitory neurotransmission by GABAA receptors having α2,3-subunits ameliorates behavioral deficits in a mouse model of autism.
      ,
      • Gogolla N.
      • Takesian A.E.
      • Feng G.
      • Fagiolini M.
      • Hensch T.K.
      Sensory integration in mouse insular cortex reflects GABA circuit maturation.
      ,
      • Defensor E.B.
      • Pearson B.L.
      • Pobbe R.L.
      • Bolivar V.J.
      • Blanchard D.C.
      • Blanchard R.J.
      A novel social proximity test suggests patterns of social avoidance and gaze aversion-like behavior in BTBR T+ tf/J mice.
      ), Cntnap2 (
      • Penagarikano O.
      • Abrahams B.S.
      • Herman E.I.
      • Winden K.D.
      • Gdalyahu A.
      • Dong H.
      • et al.
      Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits.
      ,
      • Jurgensen S.
      • Castillo P.E.
      Selective dysregulation of hippocampal inhibition in the mouse lacking autism candidate gene CNTNAP2.
      ), Cntnap4 (
      • Karayannis T.
      • Au E.
      • Patel J.C.
      • Kruglikov I.
      • Markx S.
      • Delorme R.
      • et al.
      Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission.
      ), Dlx1/2;Scn1a+/fl (
      • Han S.
      • Tai C.
      • Westenbroek R.E.
      • Yu F.H.
      • Cheah C.S.
      • Potter G.B.
      • et al.
      Autistic-like behaviour in Scn1a+/- mice and rescue by enhanced GABA-mediated neurotransmission.
      ), Dlx5/6-Cre;Tsc1 (
      • Fu C.
      • Cawthon B.
      • Clinkscales W.
      • Bruce A.
      • Winzenburger P.
      • Ess K.C.
      GABAergic interneuron development and function is modulated by the Tsc1 gene.
      ), Fmr1 (
      • Selby L.
      • Zhang C.
      • Sun Q.Q.
      Major defects in neocortical GABAergic inhibitory circuits in mice lacking the fragile X mental retardation protein.
      ), Gad2 (GAD65) (
      • Gogolla N.
      • Takesian A.E.
      • Feng G.
      • Fagiolini M.
      • Hensch T.K.
      Sensory integration in mouse insular cortex reflects GABA circuit maturation.
      ), Mecp2 (
      • Gogolla N.
      • Takesian A.E.
      • Feng G.
      • Fagiolini M.
      • Hensch T.K.
      Sensory integration in mouse insular cortex reflects GABA circuit maturation.
      ,
      • Chao H.T.
      • Chen H.
      • Samaco R.C.
      • Xue M.
      • Chahrour M.
      • Yoo J.
      • et al.
      Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.
      ), Nkx2.1-Cre;Pten (
      • Vogt D.
      • Cho K.K.
      • Lee A.T.
      • Sohal V.S.
      • Rubenstein J.L.
      The parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles.
      ), Nlgn3 R451C (
      • Gogolla N.
      • Leblanc J.J.
      • Quast K.B.
      • Sudhof T.C.
      • Fagiolini M.
      • Hensch T.K.
      Common circuit defect of excitatory-inhibitory balance in mouse models of autism.
      ), Oxtr (
      • Sala M.
      • Braida D.
      • Lentini D.
      • Busnelli M.
      • Bulgheroni E.
      • Capurro V.
      • et al.
      Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: A neurobehavioral model of autism.
      ), Pvalb (
      • Wohr M.
      • Orduz D.
      • Gregory P.
      • Moreno H.
      • Khan U.
      • Vorckel K.J.
      • et al.
      Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities.
      ), PV-Cre;ErbB4 (
      • Wen L.
      • Lu Y.S.
      • Zhu X.H.
      • Li X.M.
      • Woo R.S.
      • Chen Y.J.
      • et al.
      Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons.
      ), Pv-Cre;Mecp2 (
      • Ito-Ishida A.
      • Ure K.
      • Chen H.
      • Swann J.W.
      • Zoghbi H.Y.
      Loss of MeCP2 in parvalbumin-and somatostatin-expressing neurons in mice leads to distinct Rett syndrome-like phenotypes.
      ), PV-RFP;Shank1 (
      • Mao W.
      • Watanabe T.
      • Cho S.
      • Frost J.L.
      • Truong T.
      • Zhao X.
      • Futai K.
      Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons.
      ), Scn1a+/– (
      • Han S.
      • Tai C.
      • Westenbroek R.E.
      • Yu F.H.
      • Cheah C.S.
      • Potter G.B.
      • et al.
      Autistic-like behaviour in Scn1a+/- mice and rescue by enhanced GABA-mediated neurotransmission.
      ), Scn1a+/R1407X (
      • Ito S.
      • Ogiwara I.
      • Yamada K.
      • Miyamoto H.
      • Hensch T.K.
      • Osawa M.
      • Yamakawa K.
      Mouse with Nav1.1 haploinsufficiency, a model for Dravet syndrome, exhibits lowered sociability and learning impairment.
      ), Shank3 (exons 13–16) (
      • Gogolla N.
      • Takesian A.E.
      • Feng G.
      • Fagiolini M.
      • Hensch T.K.
      Sensory integration in mouse insular cortex reflects GABA circuit maturation.
      ), SST-Cre;Mecp2 (
      • Ito-Ishida A.
      • Ure K.
      • Chen H.
      • Swann J.W.
      • Zoghbi H.Y.
      Loss of MeCP2 in parvalbumin-and somatostatin-expressing neurons in mice leads to distinct Rett syndrome-like phenotypes.
      ), SynI (
      • Lignani G.
      • Raimondi A.
      • Ferrea E.
      • Rocchi A.
      • Paonessa F.
      • Cesca F.
      • et al.
      Epileptogenic Q555X SYN1 mutant triggers imbalances in release dynamics and short-term plasticity.
      ,
      • Heise C.
      • Taha E.
      • Murru L.
      • Ponzoni L.
      • Cattaneo A.
      • Guarnieri F.C.
      • et al.
      eEF2K/eEF2 Pathway controls the excitation/inhibition balance and susceptibility to epileptic seizures [published online ahead of print Mar 21].
      ), Ube3a (
      • Wallace M.L.
      • Burette A.C.
      • Weinberg R.J.
      • Philpot B.D.
      Maternal loss of Ube3a produces an excitatory/inhibitory imbalance through neuron type-specific synaptic defects.
      ), Viaat-Cre;Mecp2 (
      • Chao H.T.
      • Chen H.
      • Samaco R.C.
      • Xue M.
      • Chahrour M.
      • Yoo J.
      • et al.
      Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.
      ), VPA mice (
      • Gogolla N.
      • Leblanc J.J.
      • Quast K.B.
      • Sudhof T.C.
      • Fagiolini M.
      • Hensch T.K.
      Common circuit defect of excitatory-inhibitory balance in mouse models of autism.
      )
      Glial CellsGfap-Cre;ERT2;Mecp2lox-stop/y (
      • Lioy D.T.
      • Garg S.K.
      • Monaghan C.E.
      • Raber J.
      • Foust K.D.
      • Kaspar B.K.
      • et al.
      A role for glia in the progression of Rett’s syndrome.
      ), Gfap-Cre;Pten (
      • Fraser M.M.
      • Bayazitov I.T.
      • Zakharenko S.S.
      • Baker S.J.
      Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities.
      ), Glast-CreERT2;Glt1 (
      • Aida T.
      • Yoshida J.
      • Nomura M.
      • Tanimura A.
      • Iino Y.
      • Soma M.
      • et al.
      Astroglial glutamate transporter deficiency increases synaptic excitability and leads to pathological repetitive behaviors in mice.
      ), Lysm-Cre;Mecp2lox-stop/y (
      • Derecki N.C.
      • Cronk J.C.
      • Lu Z.
      • Xu E.
      • Abbott S.B.
      • Guyenet P.G.
      • Kipnis J.
      Wild-type microglia arrest pathology in a mouse model of Rett syndrome.
      )
      Intrinsic Neuronal ExcitabilityNestin-Cre;Foxp1 (
      • Bacon C.
      • Schneider M.
      • Le Magueresse C.
      • Froehlich H.
      • Sticht C.
      • Gluch C.
      • et al.
      Brain-specific Foxp1 deletion impairs neuronal development and causes autistic-like behaviour.
      ), Fmr1 (
      • Zhang Y.
      • Bonnan A.
      • Bony G.
      • Ferezou I.
      • Pietropaolo S.
      • Ginger M.
      • et al.
      Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1(-/y) mice.
      ), Pv-Cre;ErbB4 (
      • Tan G.H.
      • Liu Y.Y.
      • Hu X.L.
      • Yin D.M.
      • Mei L.
      • Xiong Z.Q.
      Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons.
      ,
      • Li K.X.
      • Lu Y.M.
      • Xu Z.H.
      • Zhang J.
      • Zhu J.M.
      • Zhang J.M.
      • et al.
      Neuregulin 1 regulates excitability of fast-spiking neurons through Kv1.1 and acts in epilepsy.
      ), Shank3 (exons 13–16) (
      • Yi F.
      • Danko T.
      • Botelho S.C.
      • Patzke C.
      • Pak C.
      • Wernig M.
      • Sudhof T.C.
      Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons.
      )
      Homeostatic Synaptic PlasticityFmr1 (
      • Soden M.E.
      • Chen L.
      Fragile X protein FMRP is required for homeostatic plasticity and regulation of synaptic strength by retinoic acid.
      ,
      • Vislay R.L.
      • Martin B.S.
      • Olmos-Serrano J.L.
      • Kratovac S.
      • Nelson D.L.
      • Corbin J.G.
      • Huntsman M.M.
      Homeostatic responses fail to correct defective amygdala inhibitory circuit maturation in fragile X syndrome.
      ), Mecp2 (
      • Blackman M.P.
      • Djukic B.
      • Nelson S.B.
      • Turrigiano G.G.
      A critical and cell-autonomous role for MeCP2 in synaptic scaling up.
      ,
      • Qiu Z.
      • Sylwestrak E.L.
      • Lieberman D.N.
      • Zhang Y.
      • Liu X.Y.
      • Ghosh A.
      The Rett syndrome protein MeCP2 regulates synaptic scaling.
      ,
      • Zhong X.
      • Li H.
      • Chang Q.
      MeCP2 phosphorylation is required for modulating synaptic scaling through mGluR5.
      )
      Temporal E/I RegulationCreERT2;MECP2 and TG;Mecp2lox/y (
      • Sztainberg Y.
      • Chen H.M.
      • Swann J.W.
      • Hao S.
      • Tang B.
      • Wu Z.
      • et al.
      Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides.
      ), CreERT2;Syngap1+/lox-stop (
      • Aceti M.
      • Creson T.K.
      • Vaissiere T.
      • Rojas C.
      • Huang W.C.
      • Wang Y.X.
      • et al.
      Syngap1 haploinsufficiency damages a postnatal critical period of pyramidal cell structural maturation linked to cortical circuit assembly.
      ), CreEsr1*;Mecp2lox-stop/y (
      • Guy J.
      • Gan J.
      • Selfridge J.
      • Cobb S.
      • Bird A.
      Reversal of neurological defects in a mouse model of Rett syndrome.
      ), CreEsr1*;Ube3aStop/p (
      • Silva-Santos S.
      • van Woerden G.M.
      • Bruinsma C.F.
      • Mientjes E.
      • Jolfaei M.A.
      • Distel B.
      • et al.
      Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model.
      ), Fmr1 (
      • Tyzio R.
      • Nardou R.
      • Ferrari D.C.
      • Tsintsadze T.
      • Shahrokhi A.
      • Eftekhari S.
      • et al.
      Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring.
      ,
      • Eftekhari S.
      • Shahrokhi A.
      • Tsintsadze V.
      • Nardou R.
      • Brouchoud C.
      • Conesa M.
      • et al.
      Response to Comment on “Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring.”.
      ), Nlgn3stop-tetO;Pcp2tTA (
      • Baudouin S.J.
      • Gaudias J.
      • Gerharz S.
      • Hatstatt L.
      • Zhou K.
      • Punnakkal P.
      • et al.
      Shared synaptic pathophysiology in syndromic and nonsyndromic rodent models of autism.
      ), VPA rats (
      • Tyzio R.
      • Nardou R.
      • Ferrari D.C.
      • Tsintsadze T.
      • Shahrokhi A.
      • Eftekhari S.
      • et al.
      Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring.
      ,
      • Eftekhari S.
      • Shahrokhi A.
      • Tsintsadze V.
      • Nardou R.
      • Brouchoud C.
      • Conesa M.
      • et al.
      Response to Comment on “Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring.”.
      )
      Candidate mechanisms involved in causing E/I imbalances in some animal models of ASD. In some cases, more than one mechanism appears to apply to the same mouse model, possibly due to multiple effects of a single mutation or homeostatic interplay among different mechanisms. Additional studies may be needed to determine whether certain mechanisms listed here represent primary changes and, hence, fundamental pathogenic mechanisms. Heterozygosity and conditional gene deletion or re-expression are indicated; all other gene names without additional identifiers represent homozygosity (–/– or fl/fl) or X chromosomal/maternal deletion (Mecp2–/y;Ube3am–/p+). Full names of the genes and their known functions are as follows: Baiap2 (brain-specific angiogenesis inhibitor 1-associated protein 2; also known as IRSp53; excitatory postsynaptic adaptor and scaffolding protein); Cntnap2/4 (contactin-associated protein-like 2/4; a member of the neurexin family of cell protein 2); Eif4ebp2 (a member of the eukaryotic translation initiation factor 4E binding protein family; bind eIF4E and inhibit translation initiation); ErbB4 (erb-b2 receptor tyrosine kinase 4; a receptor for neuregulins with tyrosine kinase activity); Fmr1 (fragile X mental retardation 1; an RNA-binding protein that regulates messenger RNA trafficking); Foxp1 (forkhead box P1; a transcription factor); Gabrb3 (gamma-aminobutyric acid A receptor subunit beta 3; a GABA receptor subunit); Gad2 (glutamic acid decarboxylase 2; also known as GAD65; a GABA-synthesizing enzyme); Glt1 (solute carrier family 1 [glial high affinity glutamate transporter], member 2; also known as Sla1a2 or EAAT2, a glutamate transporter); Grid1 (glutamate receptor, ionotropic, delta 1; also known as GluD1; a subunit of glutamate receptors); Grin1 (glutamate ionotropic receptor NMDA type subunit 1; also known as GluN1; an NMDA receptor subunit); Mecp2 (methyl CpG binding protein 2; a transcription factor that binds to methylated DNA); Nf1 (neurofibromin 1; a negative regulator of ras signaling); Nlgn1/2/3 (neuroligin 1/2/3; a synaptic cell adhesion molecule); Oxtr (oxytocin receptor); Pten (phosphatase and tensin homolog; a phosphatase for phosphoinositides); Pvalb (parvalbumin; a calcium ion-binding protein); Scn1a (sodium voltage-gated channel alpha subunit 1; a subunit of voltage-dependent sodium channels); Shank1/2/3 (excitatory postsynaptic scaffolding proteins); Syngap1 (synaptic Ras GTPase activating protein 1, excitatory postsynaptic scaffolding protein with GTPase-activating protein activity); SynI (synapsin I; a protein that associates with synaptic vesicles); Tbr1 (T-box, brain 1; a transcription factor); Tsc1/2 (tuberous sclerosis 1; a growth inhibitory protein); Ube3a (ubiquitin protein ligase E3A; an E3 ubiquitin-protein ligase).
      AMPAR, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor; E/I, excitation/inhibition; GABA, gamma-aminobutyric acid; GTPase, guanosine triphosphatase; mGluR, metabotropic glutamate receptor; NMDAR, N-methyl-D-aspartate receptor; USV, ultrasonic vocalization; VPA, valproic acid.

      Excitatory Synapse Development

      Cell adhesion molecules organize synapse development through transsynaptic adhesion and synaptic protein recruitment. Neuroligins and neurexins are prototypical members (
      • Sudhof T.C.
      Neuroligins and neurexins link synaptic function to cognitive disease.
      ), and many additional molecules have recently been identified. Given their critical roles in synapse and circuit development, it is no wonder that neuroligin and neurexin genes have been among the first ASD-related genes identified in early autism studies (
      • Sudhof T.C.
      Neuroligins and neurexins link synaptic function to cognitive disease.
      ). Contrary to initial expectations, however, neuroligin/neurexin knockout in mice did not induce significant changes in synapse number, except in a few specific brain regions; instead, it substantially modified synaptic functions (
      • Sudhof T.C.
      Neuroligins and neurexins link synaptic function to cognitive disease.
      ), which may also contribute to impaired synaptic development in ASDs.
      A recent study has shown that neuroligin expression can be altered indirectly. Knockout of 4E-BP2, known to inhibit eIF4E in the mechanistic target of rapamycin (mTOR) pathway in mice (Eif4ebp2, a member of the eukaryotic translation initiation factor 4E binding protein family), upregulates neuroligins (all four known isoforms), increases hippocampal synaptic E/I ratio, and induces autistic-like behaviors (
      • Gkogkas C.G.
      • Khoutorsky A.
      • Ran I.
      • Rampakakis E.
      • Nevarko T.
      • Weatherill D.B.
      • et al.
      Autism-related deficits via dysregulated eIF4E-dependent translational control.
      ). Pharmacologic inhibition of eIF4E, or knockdown of neuroligin-1 (Nlgn1) but not neuroligin-2 (Nlgn2), which are excitatory and inhibitory synapse specific, respectively (
      • Sudhof T.C.
      Neuroligins and neurexins link synaptic function to cognitive disease.
      ), normalizes the E/I ratio and rescues autistic-like behaviors.

      AMPA receptors

      Glutamatergic dysfunction involving alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-D-aspartate (NMDA), and metabotropic glutamate (mGluR) receptors (AMPARs, NMDARs, and mGluRs) alters E/I balance. Supporting the role of AMPARs, social deficits in BTBR mice, an inbred mouse strain modeling ASD (
      • Silverman J.L.
      • Yang M.
      • Lord C.
      • Crawley J.N.
      Behavioural phenotyping assays for mouse models of autism.
      ), are rescued by the AMPAR-activator ampakine (
      • Silverman J.L.
      • Oliver C.F.
      • Karras M.N.
      • Gastrell P.T.
      • Crawley J.N.
      AMPAKINE enhancement of social interaction in the BTBR mouse model of autism.
      ). Ampakine also rescues impaired long-term potentiation (LTP) and long-term memory in Ube3a-deficient mice (Ube3am–/p+) that lack the maternal copy of an E3 ubiquitin ligase gene (
      • Baudry M.
      • Kramar E.
      • Xu X.
      • Zadran H.
      • Moreno S.
      • Lynch G.
      • et al.
      Ampakines promote spine actin polymerization, long-term potentiation, and learning in a mouse model of Angelman syndrome.
      ), a model of Angelman syndrome, characterized by intellectual disability, absence of speech, seizure, ataxia, and frequent laughter and smiling (
      • Jiang Y.H.
      • Armstrong D.
      • Albrecht U.
      • Atkins C.M.
      • Noebels J.L.
      • Eichele G.
      • et al.
      Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation.
      ).
      Mice heterozygous for Shank3 (exons 4–9 deletion), an excitatory postsynaptic scaffold (
      • Sheng M.
      • Kim E.
      The postsynaptic organization of synapses.
      ), show reduced evoked AMPAR-mediated excitatory synaptic transmission, suppressed LTP, and impaired motor function (
      • Bozdagi O.
      • Sakurai T.
      • Papapetrou D.
      • Wang X.
      • Dickstein D.L.
      • Takahashi N.
      • et al.
      Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication.
      ). These phenotypes are rescued by insulin-like growth factor 1 (IGF-1) (
      • Bozdagi O.
      • Tavassoli T.
      • Buxbaum J.D.
      Insulin-like growth factor-1 rescues synaptic and motor deficits in a mouse model of autism and developmental delay.
      ), known to activate AMPARs, but not NMDARs, through the PI3K pathway (
      • Ramsey M.M.
      • Adams M.M.
      • Ariwodola O.J.
      • Sonntag W.E.
      • Weiner J.L.
      Functional characterization of des-IGF-1 action at excitatory synapses in the CA1 region of rat hippocampus.
      ). Similar reductions in evoked AMPAR transmission are observed in other Shank3-mutant mice carrying different exon deletions (
      • Peca J.
      • Feliciano C.
      • Ting J.T.
      • Wang W.
      • Wells M.F.
      • Venkatraman T.N.
      • et al.
      Shank3 mutant mice display autistic-like behaviours and striatal dysfunction.
      ,
      • Lee J.
      • Chung C.
      • Ha S.
      • Lee D.
      • Kim D.Y.
      • Kim H.
      • Kim E.
      Shank3-mutant mice lacking exon 9 show altered excitation/inhibition balance, enhanced rearing, and spatial memory deficit.
      ,
      • Speed H.E.
      • Kouser M.
      • Xuan Z.
      • Reimers J.M.
      • Ochoa C.F.
      • Gupta N.
      • et al.
      Autism-associated insertion mutation (InsG) of Shank3 exon 21 causes impaired synaptic transmission and behavioral deficits.
      ,
      • Kouser M.
      • Speed H.E.
      • Dewey C.M.
      • Reimers J.M.
      • Widman A.J.
      • Gupta N.
      • et al.
      Loss of predominant Shank3 isoforms results in hippocampus-dependent impairments in behavior and synaptic transmission.
      ), although two studies on Shank3 mice report normal AMPAR transmission (
      • Wang X.
      • McCoy P.A.
      • Rodriguiz R.M.
      • Pan Y.
      • Je H.S.
      • Roberts A.C.
      • et al.
      Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3.
      ,
      • Jaramillo T.C.
      • Speed H.E.
      • Xuan Z.
      • Reimers J.M.
      • Liu S.
      • Powell C.M.
      Altered striatal synaptic function and abnormal behaviour in Shank3 exon4-9 deletion mouse model of autism.
      ). Conversely, an increase in spontaneous AMPAR transmission is observed in mice carrying a Shank3 duplication, and seizure and mania-like behaviors in these mice are corrected by the mood-stabilizing agent valproic acid (VPA) (
      • Han K.
      • Holder Jr, J.L.
      • Schaaf C.P.
      • Lu H.
      • Chen H.
      • Kang H.
      • et al.
      SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties.
      ).
      Mice lacking the transcription regulator MeCP2, modeling Rett syndrome, which is characterized by loss of language and motor skills, show reduced spontaneous and evoked AMPAR transmission and excitatory synaptic connectivity (
      • Nelson E.D.
      • Kavalali E.T.
      • Monteggia L.M.
      MeCP2-dependent transcriptional repression regulates excitatory neurotransmission.
      ,
      • Dani V.S.
      • Chang Q.
      • Maffei A.
      • Turrigiano G.G.
      • Jaenisch R.
      • Nelson S.B.
      Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome.
      ). Conversely, mice with neuron-specific Mecp2 overexpression show increased spontaneous AMPAR transmission (
      • Na E.S.
      • Nelson E.D.
      • Adachi M.
      • Autry A.E.
      • Mahgoub M.A.
      • Kavalali E.T.
      • Monteggia L.M.
      A mouse model for MeCP2 duplication syndrome: MeCP2 overexpression impairs learning and memory and synaptic transmission.
      ) that is in line with dose-dependent changes in spontaneous and evoked AMPAR transmission in autaptic hippocampal neurons from transgenic mice (
      • Chao H.T.
      • Zoghbi H.Y.
      • Rosenmund C.
      MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number.
      ). Similar to Shank3 mice, IGF-1 treatment of Mecp2 mice partially rescues the reduced spontaneous excitatory transmission, spine density, and PSD-95 levels (an excitatory postsynaptic scaffold) (
      • Tropea D.
      • Giacometti E.
      • Wilson N.R.
      • Beard C.
      • McCurry C.
      • Fu D.D.
      • et al.
      Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice.
      ).
      Syngap1 is an excitatory postsynaptic guanosine triphosphatase-activating protein (Ras-GAP) implicated in intellectual disability and ASD (
      • Volk L.
      • Chiu S.L.
      • Sharma K.
      • Huganir R.L.
      Glutamate synapses in human cognitive disorders.
      ). Syngap1 heterozygous mice show increased AMPAR transmission, precocious spine development, and hyperactive circuits in the hippocampus, and reduced seizure threshold at ~postnatal day 14 (P14) but not at ~P7, P21, or P42 (
      • Clement J.P.
      • Aceti M.
      • Creson T.K.
      • Ozkan E.D.
      • Shi Y.
      • Reish N.J.
      • et al.
      Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses.
      ). Syngap1 haploinsufficiency restricted to forebrain glutamatergic neurons (Emx1-Cre), but not GABAergic neurons (glutamic acid decarboxylase 2 [Gad2-Cre]), induces similar phenotypes (
      • Ozkan E.D.
      • Creson T.K.
      • Kramar E.A.
      • Rojas C.
      • Seese R.R.
      • Babyan A.H.
      • et al.
      Reduced cognition in Syngap1 mutants is caused by isolated damage within developing forebrain excitatory neurons.
      ). In addition, Syngap1 re-expression in forebrain glutamatergic neurons (Emx1-Cre;Syngap1+/lox-stop), but not in GABAergic neurons (Gad2-Cre;Syngap1+/lox-stop), rescues cognitive and emotional deficits (
      • Ozkan E.D.
      • Creson T.K.
      • Kramar E.A.
      • Rojas C.
      • Seese R.R.
      • Babyan A.H.
      • et al.
      Reduced cognition in Syngap1 mutants is caused by isolated damage within developing forebrain excitatory neurons.
      ). Therefore, an early, excessive excitatory transmission in glutamatergic neurons impairs brain functions in Syngap1 mice.

      NMDARs

      Animal models of ASDs exhibit NMDAR dysfunction and behavioral abnormalities that respond to NMDAR-modulating reagents (
      • Lee E.J.
      • Choi S.Y.
      • Kim E.
      NMDA receptor dysfunction in autism spectrum disorders.
      ). Directly supporting the importance of NMDARs, mice with ~85% downregulation of the glutamate ionotropic 1 (GluN1) subunit of NMDARs (Grin1) show social deficits and repetitive behavior (
      • Gandal M.J.
      • Anderson R.L.
      • Billingslea E.N.
      • Carlson G.C.
      • Roberts T.P.
      • Siegel S.J.
      Mice with reduced NMDA receptor expression: More consistent with autism than schizophrenia?.
      ).
      Nlgn1-mutant mice display NMDAR hypofunction and increased grooming responsive to the NMDAR agonist D-cycloserine (
      • Blundell J.
      • Blaiss C.A.
      • Etherton M.R.
      • Espinosa F.
      • Tabuchi K.
      • Walz C.
      • et al.
      Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior.
      ). In addition, Shank2 mice (exons 6–7) show NMDAR hypofunction and social deficits rescued by D-cycloserine (
      • Won H.
      • Lee H.R.
      • Gee H.Y.
      • Mah W.
      • Kim J.I.
      • Lee J.
      • et al.
      Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function.
      ), or clioquinol, a zinc chelator that enhances NMDAR function through transsynaptic zinc delivery (
      • Lee E.J.
      • Lee H.
      • Huang T.N.
      • Chung C.
      • Shin W.
      • Kim K.
      • et al.
      Trans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation.
      ). Notably, other Shank2-mutant mice (exon 7) show enhanced NMDAR function (
      • Schmeisser M.J.
      • Ey E.
      • Wegener S.
      • Bockmann J.
      • Stempel V.
      • Kuebler A.
      • et al.
      Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2.
      ), suggesting that different mutations in the same gene may cause NMDAR dysfunction in opposite directions. Mice heterozygous for Tbr1, encoding a transcription factor with targets that include the GluN2B subunit of NMDARs, show NMDAR hypofunction and social deficits responsive to D-cycloserine (
      • Huang T.N.
      • Chuang H.C.
      • Chou W.H.
      • Chen C.Y.
      • Wang H.F.
      • Chou S.J.
      • Hsueh Y.P.
      Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality.
      ) and clioquinol (
      • Lee E.J.
      • Lee H.
      • Huang T.N.
      • Chung C.
      • Shin W.
      • Kim K.
      • et al.
      Trans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation.
      ).
      Other Shank3 mice (Shank3+/ΔC(exon21)) show NMDAR hypofunction and social deficits responsive to inhibition of cofilin (
      • Duffney L.J.
      • Zhong P.
      • Wei J.
      • Matas E.
      • Cheng J.
      • Qin L.
      • et al.
      Autism-like deficits in Shank3-deficient mice are rescued by targeting actin regulators.
      ), a negative actin regulator. In addition, two different Shank3 mouse lines (exons 4–9 and e21G) show similar NMDAR hypofunction (
      • Speed H.E.
      • Kouser M.
      • Xuan Z.
      • Reimers J.M.
      • Ochoa C.F.
      • Gupta N.
      • et al.
      Autism-associated insertion mutation (InsG) of Shank3 exon 21 causes impaired synaptic transmission and behavioral deficits.
      ,
      • Kouser M.
      • Speed H.E.
      • Dewey C.M.
      • Reimers J.M.
      • Widman A.J.
      • Gupta N.
      • et al.
      Loss of predominant Shank3 isoforms results in hippocampus-dependent impairments in behavior and synaptic transmission.
      ,
      • Jaramillo T.C.
      • Speed H.E.
      • Xuan Z.
      • Reimers J.M.
      • Liu S.
      • Powell C.M.
      Altered striatal synaptic function and abnormal behaviour in Shank3 exon4-9 deletion mouse model of autism.
      ), although rescue attempts were not made. Several other animal models, including Grid1, BTBR, and BALB/c mice, and rats with low play-related prosocial ultrasonic vocalizations, show autistic-like behaviors that are rescued by D-cycloserine or other NMDAR agonists (
      • Yadav R.
      • Hillman B.G.
      • Gupta S.C.
      • Suryavanshi P.
      • Bhatt J.M.
      • Pavuluri R.
      • et al.
      Deletion of glutamate delta-1 receptor in mouse leads to enhanced working memory and deficit in fear conditioning.
      ,
      • Burket J.A.
      • Benson A.D.
      • Tang A.H.
      • Deutsch S.I.
      D-Cycloserine improves sociability in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorders with altered Ras/Raf/ERK1/2 signaling.
      ,
      • Benson A.D.
      • Burket J.A.
      • Deutsch S.I.
      Balb/c mice treated with D-cycloserine arouse increased social interest in conspecifics.
      ,
      • Deutsch S.I.
      • Pepe G.J.
      • Burket J.A.
      • Winebarger E.E.
      • Herndon A.L.
      • Benson A.D.
      D-cycloserine improves sociability and spontaneous stereotypic behaviors in 4-week old mice.
      ,
      • Burgdorf J.
      • Moskal J.R.
      • Brudzynski S.M.
      • Panksepp J.
      Rats selectively bred for low levels of play-induced 50 kHz vocalizations as a model for autism spectrum disorders: a role for NMDA receptors.
      ), although NMDAR function remains to be investigated.
      At the other end of the spectrum, excessive NMDAR function also appears to cause autistic-like behaviors. Rats prenatally exposed to VPA show increased NMDAR levels, enhanced NMDAR-dependent LTP, and hyperconnected local neocortical circuits (
      • Rinaldi T.
      • Perrodin C.
      • Markram H.
      Hyper-connectivity and hyper-plasticity in the medial prefrontal cortex in the valproic Acid animal model of autism.
      ,
      • Rinaldi T.
      • Kulangara K.
      • Antoniello K.
      • Markram H.
      Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid.
      ). The autistic-like behaviors in VPA rodents are rescued by memantine (
      • Kim K.C.
      • Lee D.K.
      • Go H.S.
      • Kim P.
      • Choi C.S.
      • Kim J.W.
      • et al.
      Pax6-dependent cortical glutamatergic neuronal differentiation regulates autism-like behavior in prenatally valproic acid-exposed rat offspring.
      ,
      • Kang J.
      • Kim E.
      Suppression of NMDA receptor function in mice prenatally exposed to valproic acid improves social deficits and repetitive behaviors.
      ). In addition, mice lacking IRSp53, or Baiap2, an abundant excitatory postsynaptic scaffold, show NMDAR hyperfunction and social and cognitive impairments responsive to memantine (
      • Chung W.
      • Choi S.Y.
      • Lee E.
      • Park H.
      • Kang J.
      • Park H.
      • et al.
      Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression.
      ). These results collectively suggest that deviation of NMDAR function in either direction leads to autistic-like behaviors (
      • Lee E.J.
      • Choi S.Y.
      • Kim E.
      NMDA receptor dysfunction in autism spectrum disorders.
      ).

      mGluRs

      Metabotropic glutamate receptors have long been implicated in ASDs (
      • Zoghbi H.Y.
      • Bear M.F.
      Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities.
      ). A well-known example is mGluR5 hyperfunction in mice lacking FMRP (Fmr1y/–), an RNA-binding protein implicated in fragile X syndrome (
      • Richter J.D.
      • Bassell G.J.
      • Klann E.
      Dysregulation and restoration of translational homeostasis in fragile X syndrome.
      ,
      • Fernandez E.
      • Rajan N.
      • Bagni C.
      The FMRP regulon: from targets to disease convergence.
      ). These mice show behavioral abnormalities that are rescued by mGluR5 antagonists (
      • Michalon A.
      • Bruns A.
      • Risterucci C.
      • Honer M.
      • Ballard T.M.
      • Ozmen L.
      • et al.
      Chronic metabotropic glutamate receptor 5 inhibition corrects local alterations of brain activity and improves cognitive performance in fragile X mice.
      ,
      • Michalon A.
      • Sidorov M.
      • Ballard T.M.
      • Ozmen L.
      • Spooren W.
      • Wettstein J.G.
      • et al.
      Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice.
      ,
      • Yuskaitis C.J.
      • Mines M.A.
      • King M.K.
      • Sweatt J.D.
      • Miller C.A.
      • Jope R.S.
      Lithium ameliorates altered glycogen synthase kinase-3 and behavior in a mouse model of fragile X syndrome.
      ,
      • Yan Q.J.
      • Rammal M.
      • Tranfaglia M.
      • Bauchwitz R.P.
      Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP.
      ). In addition, in BTBR mice, mGluR5 inhibition rescues social deficits and repetitive behaviors (
      • Silverman J.L.
      • Smith D.G.
      • Rizzo S.J.
      • Karras M.N.
      • Turner S.M.
      • Tolu S.S.
      • et al.
      Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism.
      ,
      • Silverman J.L.
      • Tolu S.S.
      • Barkan C.L.
      • Crawley J.N.
      Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP.
      ), as well as hippocampus-dependent memory (
      • Seese R.R.
      • Maske A.R.
      • Lynch G.
      • Gall C.M.
      Long-term memory deficits are associated with elevated synaptic ERK1/2 activation and reversed by mGluR5 antagonism in an animal model of autism.
      ).
      The causal role of mGluR5 hyperfunction is further supported by genetic rescue of mGluR5 signaling. Suppressing exaggerated mGluR5 signaling in Fmr1 mice by crossing them with mGluR5 heterozygous mice (Grm5+/–) rescues disease-related synaptic, biochemical, and behavioral phenotypes (
      • Dolen G.
      • Osterweil E.
      • Rao B.S.
      • Smith G.B.
      • Auerbach B.D.
      • Chattarji S.
      • Bear M.F.
      Correction of fragile X syndrome in mice.
      ). More recently, a genetic cross of Fmr1 mice with Tsc2 heterozygous mice (Tsc2+/–), which display reduced mGluR5 signaling, rescued all disease-related phenotypes (
      • Auerbach B.D.
      • Osterweil E.K.
      • Bear M.F.
      Mutations causing syndromic autism define an axis of synaptic pathophysiology.
      ).
      Results obtained in studies related to glutamate receptor malfunctions should be interpreted with care because the three glutamate receptors can influence each other. For instance, it is well known that AMPARs are regulated by NMDARs and mGluRs. In addition, NMDARs and mGluRs can exert synergistic actions (
      • Jia Z.
      • Lu Y.
      • Henderson J.
      • Taverna F.
      • Romano C.
      • Abramow-Newerly W.
      • et al.
      Selective abolition of the NMDA component of long-term potentiation in mice lacking mGluR5.
      ,
      • Alagarsamy S.
      • Marino M.J.
      • Rouse S.T.
      • Gereau 4th, R.W.
      • Heinemann S.F.
      • Conn P.J.
      Activation of NMDA receptors reverses desensitization of mGluR5 in native and recombinant systems.
      ); social deficits in Shank2 mice (exons 6–7), displaying NMDAR hypofunction, are rescued by indirectly stimulating NMDARs using the mGluR5 agonist CDPPB (
      • Won H.
      • Lee H.R.
      • Gee H.Y.
      • Mah W.
      • Kim J.I.
      • Lee J.
      • et al.
      Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function.
      ).

      Signaling Pathways

      Signaling pathways downstream or upstream of synaptic receptors and channels can regulate E/I balance. The mTOR pathway, known to be activated by NMDARs, mGluRs, and receptor tyrosine kinases, has been implicated in fragile X syndrome and ASDs (
      • Huber K.M.
      • Klann E.
      • Costa-Mattioli M.
      • Zukin R.S.
      Dysregulation of mammalian target of rapamycin signaling in mouse models of autism.
      ). For instance, the mTOR inhibitor rapamycin rescues autistic-like phenotypes in animal models with heightened mTOR signaling, including Nse-Cre;Pten (
      • Zhou J.
      • Blundell J.
      • Ogawa S.
      • Kwon C.H.
      • Zhang W.
      • Sinton C.
      • et al.
      Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice.
      ), Tsc1 (Pcp2/L7-Cre;Tsc1, Emx1-Cre;Tsc1) (
      • Tsai P.T.
      • Hull C.
      • Chu Y.
      • Greene-Colozzi E.
      • Sadowski A.R.
      • Leech J.M.
      • et al.
      Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice.
      ,
      • Cambiaghi M.
      • Cursi M.
      • Magri L.
      • Castoldi V.
      • Comi G.
      • Minicucci F.
      • et al.
      Behavioural and EEG effects of chronic rapamycin treatment in a mouse model of tuberous sclerosis complex.
      ), Tsc2 (Tsc2+/–) (
      • Ehninger D.
      • Han S.
      • Shilyansky C.
      • Zhou Y.
      • Li W.
      • Kwiatkowski D.J.
      • et al.
      Reversal of learning deficits in a Tsc2+/– mouse model of tuberous sclerosis.
      ,
      • Sato A.
      • Kasai S.
      • Kobayashi T.
      • Takamatsu Y.
      • Hino O.
      • Ikeda K.
      • Mizuguchi M.
      Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex.
      ,
      • Tang G.
      • Gudsnuk K.
      • Kuo S.H.
      • Cotrina M.L.
      • Rosoklija G.
      • Sosunov A.
      • et al.
      Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits.
      ), and Ube3a (
      • Sun J.
      • Liu Y.
      • Moreno S.
      • Baudry M.
      • Bi X.
      Imbalanced mechanistic target of rapamycin C1 and C2 activity in the cerebellum of Angelman syndrome mice impairs motor function.
      ). In some studies, the most downstream proteins in the mTOR pathway are targeted for rescue; examples include eIF4E in Eif4ebp2-deficient mice (
      • Gkogkas C.G.
      • Khoutorsky A.
      • Ran I.
      • Rampakakis E.
      • Nevarko T.
      • Weatherill D.B.
      • et al.
      Autism-related deficits via dysregulated eIF4E-dependent translational control.
      ), and S6K1 in Fmr1 mice (
      • Bhattacharya A.
      • Kaphzan H.
      • Alvarez-Dieppa A.C.
      • Murphy J.P.
      • Pierre P.
      • Klann E.
      Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice.
      ).
      Actin-modulatory pathways, important for actin-rich excitatory synapses, have also been implicated. Ampakine, which rescues LTP and memory phenotypes in Ube3a mice, stabilizes synaptic actin filaments during LTP (
      • Baudry M.
      • Kramar E.
      • Xu X.
      • Zadran H.
      • Moreno S.
      • Lynch G.
      • et al.
      Ampakines promote spine actin polymerization, long-term potentiation, and learning in a mouse model of Angelman syndrome.
      ). In addition, pharmacologic or genetic modulation of the actin-regulatory proteins PAK and cofilin rescues autistic-like behaviors in Nf1 (neurofibromatosis type 1; Nf1+/–) (
      • Molosh A.I.
      • Johnson P.L.
      • Spence J.P.
      • Arendt D.
      • Federici L.M.
      • Bernabe C.
      • et al.
      Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase.
      ), Shank3 (Shank3+/ΔC) (
      • Duffney L.J.
      • Zhong P.
      • Wei J.
      • Matas E.
      • Cheng J.
      • Qin L.
      • et al.
      Autism-like deficits in Shank3-deficient mice are rescued by targeting actin regulators.
      ), and Fmr1 (
      • Dolan B.M.
      • Duron S.G.
      • Campbell D.A.
      • Vollrath B.
      • Shankaranarayana Rao B.S.
      • Ko H.Y.
      • et al.
      Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486.
      ) mice.
      Dopamine receptor agonists/antagonists and 5-hydroxytryptamine rescue autistic-like behaviors in Cntnap2 (encoding contactin-associated protein-like 2) (
      • Penagarikano O.
      • Abrahams B.S.
      • Herman E.I.
      • Winden K.D.
      • Gdalyahu A.
      • Dong H.
      • et al.
      Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits.
      ), Cntnap4 (
      • Karayannis T.
      • Au E.
      • Patel J.C.
      • Kruglikov I.
      • Markx S.
      • Delorme R.
      • et al.
      Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission.
      ), Fmr1 (
      • Lim C.S.
      • Hoang E.T.
      • Viar K.E.
      • Stornetta R.L.
      • Scott M.M.
      • Zhu J.J.
      Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model.
      ), and BTBR (
      • Amodeo D.A.
      • Jones J.H.
      • Sweeney J.A.
      • Ragozzino M.E.
      Risperidone and the 5-HT2A receptor antagonist M100907 improve probabilistic reversal learning in BTBR T + tf/J mice.
      ) mice, implicating monoaminergic pathways. Although rescue mechanisms in these cases are generally unclear, the Ras-PI3K-Akt pathway and GluA1-dependent synaptic plasticity have been suggested for Fmr1 mice (
      • Lim C.S.
      • Hoang E.T.
      • Viar K.E.
      • Stornetta R.L.
      • Scott M.M.
      • Zhu J.J.
      Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model.
      ).

      Inhibitory Synapse Development and Function

      GABAergic signaling is frequently altered in animal models of ASD (
      • Nelson S.B.
      • Valakh V.
      Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders.
      ,
      • Cellot G.
      • Cherubini E.
      GABAergic signaling as therapeutic target for autism spectrum disorders.
      ,
      • Sudhof T.C.
      Neuroligins and neurexins link synaptic function to cognitive disease.
      ), in line with many related human genetic variations (
      • Bourgeron T.
      The possible interplay of synaptic and clock genes in autism spectrum disorders.
      ,
      • Sudhof T.C.
      Neuroligins and neurexins link synaptic function to cognitive disease.
      ,
      • Lionel A.C.
      • Vaags A.K.
      • Sato D.
      • Gazzellone M.J.
      • Mitchell E.B.
      • Chen H.Y.
      • et al.
      Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures.
      ). Inhibitory synaptic adhesion molecules are important regulators of GABAergic signaling. Virus-mediated deletion of inhibitory synapse-specific Nlgn2 in the medial prefrontal cortex leads to delayed (6–7 postnatal weeks) decreases in inhibitory synapse density, miniature inhibitory postsynaptic current (IPSC) frequency and amplitude, and evoked IPSC input-output curves, effects that are accompanied by social and cognitive deficits (
      • Liang J.
      • Xu W.
      • Hsu Y.T.
      • Yee A.X.
      • Chen L.
      • Sudhof T.C.
      Conditional neuroligin-2 knockout in adult medial prefrontal cortex links chronic changes in synaptic inhibition to cognitive impairments.
      ). An earlier study also showed that Nlgn2 deletion in mice suppresses GABAergic and glycinergic transmission through impaired assembly of postsynaptic receptor complexes at perisomatic inhibitory synapses (
      • Poulopoulos A.
      • Aramuni G.
      • Meyer G.
      • Soykan T.
      • Hoon M.
      • Papadopoulos T.
      • et al.
      Neuroligin 2 drives postsynaptic assembly at perisomatic inhibitory synapses through gephyrin and collybistin.
      ).
      Mice lacking Nlgn3, which is present at both excitatory and inhibitory synapses and implicated in ASDs (
      • Sudhof T.C.
      Neuroligins and neurexins link synaptic function to cognitive disease.
      ), show minimal alterations in excitatory or inhibitory synapse density or function (
      • Tabuchi K.
      • Blundell J.
      • Etherton M.R.
      • Hammer R.E.
      • Liu X.
      • Powell C.M.
      • Sudhof T.C.
      A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice.
      ). However, recent studies have reported enhanced GABAergic transmission at cholecystokinin-positive basket cell synapses in the hippocampus (
      • Foldy C.
      • Malenka R.C.
      • Sudhof T.C.
      Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling.
      ) and impaired cerebellar mGluR-dependent synaptic long-term depression (
      • Baudouin S.J.
      • Gaudias J.
      • Gerharz S.
      • Hatstatt L.
      • Zhou K.
      • Punnakkal P.
      • et al.
      Shared synaptic pathophysiology in syndromic and nonsyndromic rodent models of autism.
      ).
      Intriguingly, Nlgn3 knockin mice carrying a human mutation (Nlgn3 R451C) show enhanced GABAergic transmission in the somatosensory cortex, together with increased frequency of spontaneous IPSCs and increased levels of the inhibitory synaptic proteins vesicular GABA transporter (VGAT) and gephyrin (
      • Tabuchi K.
      • Blundell J.
      • Etherton M.R.
      • Hammer R.E.
      • Liu X.
      • Powell C.M.
      • Sudhof T.C.
      A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice.
      ). In addition, the R451C knockin impairs GABAergic transmission in PV basket cell synapses, but enhances GABAergic transmission in cholecystokinin basket cell synapses in the hippocampus (
      • Foldy C.
      • Malenka R.C.
      • Sudhof T.C.
      Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling.
      ), suggesting that the same mutation induces distinct changes in GABAergic transmission in different brain regions and cell types.
      In the striatum, Nlgn3 deletion restricted to D1 medium spiny neurons (D1-MSNs), but not D2-MSNs, suppresses GABAergic transmission onto D1-MSNs (
      • Rothwell P.E.
      • Fuccillo M.V.
      • Maxeiner S.
      • Hayton S.J.
      • Gokce O.
      • Lim B.K.
      • et al.
      Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors.
      ). Importantly, re-expression of Nlgn3, or K+ channel expression causing neuronal relaxation, in Nlgn3-deficient D1-MSNs rescues GABAergic transmission and rotarod performance (
      • Rothwell P.E.
      • Fuccillo M.V.
      • Maxeiner S.
      • Hayton S.J.
      • Gokce O.
      • Lim B.K.
      • et al.
      Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors.
      ), suggesting that abnormally excited D1-MSNs cause autistic-like phenotypes.
      Altered GABA type A (GABAA) receptor levels or function would directly affect E/I balance. A deficiency of the ASD-associated β3 subunit of the GABAA receptor (Gabrb3) in mice reduces GABAA receptor levels, enhances seizure susceptibility, and induces cognitive and motor deficits (
      • DeLorey T.M.
      • Handforth A.
      • Anagnostaras S.G.
      • Homanics G.E.
      • Minassian B.A.
      • Asatourian A.
      • et al.
      Mice lacking the beta3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome.
      ,
      • Homanics G.E.
      • DeLorey T.M.
      • Firestone L.L.
      • Quinlan J.J.
      • Handforth A.
      • Harrison N.L.
      • et al.
      Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior.
      ). Reduced levels of GABAA receptor subunits are also observed in Fmr1 mice (
      • El Idrissi A.
      • Ding X.H.
      • Scalia J.
      • Trenkner E.
      • Brown W.T.
      • Dobkin C.
      Decreased GABA(A) receptor expression in the seizure-prone fragile X mouse.
      ,
      • Gantois I.
      • Vandesompele J.
      • Speleman F.
      • Reyniers E.
      • D’Hooge R.
      • Severijnen L.A.
      • et al.
      Expression profiling suggests underexpression of the GABA(A) receptor subunit delta in the fragile X knockout mouse model.
      ,
      • Adusei D.C.
      • Pacey L.K.
      • Chen D.
      • Hampson D.R.
      Early developmental alterations in GABAergic protein expression in fragile X knockout mice.
      ). Moreover, the GABAA receptor antagonist DMCM given to wild-type mice impairs social interaction (
      • Han S.
      • Tai C.
      • Jones C.J.
      • Scheuer T.
      • Catterall W.A.
      Enhancement of inhibitory neurotransmission by GABAA receptors having α2,3-subunits ameliorates behavioral deficits in a mouse model of autism.
      ).
      Tonic GABAergic transmission, involving extrasynaptic GABAA receptors, appears to be altered in ASD model animals. Fmr1 mice show reduced tonic but not phasic GABA currents in the subiculum (
      • Curia G.
      • Papouin T.
      • Seguela P.
      • Avoli M.
      Downregulation of tonic GABAergic inhibition in a mouse model of fragile X syndrome.
      ), reduced phasic and tonic GABA currents in the amygdala (
      • Olmos-Serrano J.L.
      • Paluszkiewicz S.M.
      • Martin B.S.
      • Kaufmann W.E.
      • Corbin J.G.
      • Huntsman M.M.
      Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome.
      ), and increased phasic GABA currents due to enhanced GABA release in the striatum (tonic currents were not measured) (
      • Centonze D.
      • Rossi S.
      • Mercaldo V.
      • Napoli I.
      • Ciotti M.T.
      • De Chiara V.
      • et al.
      Abnormal striatal GABA transmission in the mouse model for the fragile X syndrome.
      ), indicative of heterogeneous effects of Fmr1 deletion. Importantly, the GABA agonist 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), a selective enhancer of tonic GABA currents, rescues hyperexcitability of principal neurons in the Fmr1-deficient amygdala (
      • Olmos-Serrano J.L.
      • Paluszkiewicz S.M.
      • Martin B.S.
      • Kaufmann W.E.
      • Corbin J.G.
      • Huntsman M.M.
      Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome.
      ). Therefore, deceased GABAergic signaling, in addition to enhanced mGluR signaling, may contribute to fragile X syndrome (
      • Nelson S.B.
      • Valakh V.
      Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders.
      ,
      • Cea-Del Rio C.A.
      • Huntsman M.M.
      The contribution of inhibitory interneurons to circuit dysfunction in Fragile X Syndrome.
      ,
      • Braat S.
      • Kooy R.F.
      The GABAA receptor as a therapeutic target for neurodevelopmental disorders.
      ).
      Decreased tonic inhibition is also observed in cerebellar granule cells of Ube3a mice, which have increased levels of GABA transporter 1, a substrate of UBE3A, and reduced levels of ambient GABA (
      • Egawa K.
      • Kitagawa K.
      • Inoue K.
      • Takayama M.
      • Takayama C.
      • Saitoh S.
      • et al.
      Decreased tonic inhibition in cerebellar granule cells causes motor dysfunction in a mouse model of Angelman syndrome.
      ). These changes accompany abnormal Purkinje cell firing and cerebellar ataxia, both of which are rescued by THIP (
      • Egawa K.
      • Kitagawa K.
      • Inoue K.
      • Takayama M.
      • Takayama C.
      • Saitoh S.
      • et al.
      Decreased tonic inhibition in cerebellar granule cells causes motor dysfunction in a mouse model of Angelman syndrome.
      ). In the hippocampus, however, UBE3A deficiency enhances neuregulin-ErbB4 (Erb-B2 receptor tyrosine kinase 4) signaling and GABAergic output, and the resulting impairments in LTP in target pyramidal neurons and contextual fear memory are rescued by the ErbB inhibitor PD158780 (
      • Kaphzan H.
      • Hernandez P.
      • Jung J.I.
      • Cowansage K.K.
      • Deinhardt K.
      • Chao M.V.
      • et al.
      Reversal of impaired hippocampal long-term potentiation and contextual fear memory deficits in Angelman syndrome model mice by ErbB inhibitors.
      ), or the GABAA antagonist bicuculline (LTP rescue) (
      • Kaphzan H.
      • Hernandez P.
      • Jung J.I.
      • Cowansage K.K.
      • Deinhardt K.
      • Chao M.V.
      • et al.
      Reversal of impaired hippocampal long-term potentiation and contextual fear memory deficits in Angelman syndrome model mice by ErbB inhibitors.
      ). These results suggest that UBE3A deletion can cause region-specific changes in GABAergic signaling, which can interact with excitatory synaptic function.

      Interneurons

      GABAergic interneurons are associated with various neurological and psychiatric disorders (
      • Nelson S.B.
      • Valakh V.
      Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders.
      ,
      • Cellot G.
      • Cherubini E.
      GABAergic signaling as therapeutic target for autism spectrum disorders.
      ,
      • Marin O.
      Interneuron dysfunction in psychiatric disorders.
      ). Many ASD-associated genes are expressed in interneurons, and their mutations impair interneuronal development and input/output function, including dendritic synapse development and function, neuronal excitability and firing, nerve terminal development and function (i.e., GABA synthesis, packaging, and release), and inhibitory synapse formation with target neurons. Several of these deficits are often caused by a single gene defect.
      PV interneurons are critical regulators of gamma oscillations and are associated with various psychiatric disorders (
      • Sohal V.S.
      • Zhang F.
      • Yizhar O.
      • Deisseroth K.
      Parvalbumin neurons and gamma rhythms enhance cortical circuit performance.
      ,
      • Cardin J.A.
      • Carlen M.
      • Meletis K.
      • Knoblich U.
      • Zhang F.
      • Deisseroth K.
      • et al.
      Driving fast-spiking cells induces gamma rhythm and controls sensory responses.
      ,
      • Uhlhaas P.J.
      • Singer W.
      Neuronal dynamics and neuropsychiatric disorders: Toward a translational paradigm for dysfunctional large-scale networks.
      ). Their functional importance is supported by the impaired multisensory integration (MSI) in the insular cortex, known to exhibit reduced connectivity in ASDs (
      • Uddin L.Q.
      • Menon V.
      The anterior insula in autism: Under-connected and under-examined.
      ), observed in BTBR, Gad2(GAD65), Mecp2, and Shank3 mice (
      • Gogolla N.
      • Takesian A.E.
      • Feng G.
      • Fagiolini M.
      • Hensch T.K.
      Sensory integration in mouse insular cortex reflects GABA circuit maturation.
      ). Intriguingly, diazepam-treated adult BTBR mice show normalized MSI, whereas diazepam-treated control mice show impaired MSI (
      • Gogolla N.
      • Takesian A.E.
      • Feng G.
      • Fagiolini M.
      • Hensch T.K.
      Sensory integration in mouse insular cortex reflects GABA circuit maturation.
      ), indicative of an optimum range of PV neuron inhibition. In addition, diazepam-treated young BTBR mice show normal MSI at adult stages (
      • Gogolla N.
      • Takesian A.E.
      • Feng G.
      • Fagiolini M.
      • Hensch T.K.
      Sensory integration in mouse insular cortex reflects GABA circuit maturation.
      ), suggesting that early treatment has long-lasting effects. GABAergic interneurons other than PV such as somatostatin (SST), calretinin, and neuropeptide Y (NPY) are also important for ASDs. For instance, Mecp2 deletion restricted to PV and SST interneurons leads to distinct phenotypes; motor, sensory, memory, and social deficits in PV-Mecp2 knockout; and seizures and stereotypies in SST-Mecp2 knockout (
      • Ito-Ishida A.
      • Ure K.
      • Chen H.
      • Swann J.W.
      • Zoghbi H.Y.
      Loss of MeCP2 in parvalbumin-and somatostatin-expressing neurons in mice leads to distinct Rett syndrome-like phenotypes.
      ).
      One of the specific interneuronal defects observed in animal models is reduced cell density. PV interneuron density is decreased in mouse models, including Fmr1 (
      • Selby L.
      • Zhang C.
      • Sun Q.Q.
      Major defects in neocortical GABAergic inhibitory circuits in mice lacking the fragile X mental retardation protein.
      ), VPA (
      • Gogolla N.
      • Leblanc J.J.
      • Quast K.B.
      • Sudhof T.C.
      • Fagiolini M.
      • Hensch T.K.
      Common circuit defect of excitatory-inhibitory balance in mouse models of autism.
      ), Nlgn3 R451C (
      • Gogolla N.
      • Leblanc J.J.
      • Quast K.B.
      • Sudhof T.C.
      • Fagiolini M.
      • Hensch T.K.
      Common circuit defect of excitatory-inhibitory balance in mouse models of autism.
      ), and Cntnap2 (
      • Penagarikano O.
      • Abrahams B.S.
      • Herman E.I.
      • Winden K.D.
      • Gdalyahu A.
      • Dong H.
      • et al.
      Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits.
      ). Non-PV interneuronal density is also altered. Cntnap2 mice show reduced calretinin and NPY interneuron counts, in addition to PV interneuronal reduction (
      • Penagarikano O.
      • Abrahams B.S.
      • Herman E.I.
      • Winden K.D.
      • Gdalyahu A.
      • Dong H.
      • et al.
      Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits.
      ). Pten knockout restricted to cortical GABAergic interneuronal progenitors (Nkx2.1-Cre;Pten) preferentially decreases SST cell counts (relative to PV), leading to increases in PV-SST cell ratio and target-neuron inhibition (
      • Vogt D.
      • Cho K.K.
      • Lee A.T.
      • Sohal V.S.
      • Rubenstein J.L.
      The parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles.
      ). In addition, Tsc1 knockout in GABAergic interneuronal progenitors (Dlx5/6-Cre;Tsc1) decreases calretinin and NPY cell counts and seizure threshold (
      • Fu C.
      • Cawthon B.
      • Clinkscales W.
      • Bruce A.
      • Winzenburger P.
      • Ess K.C.
      GABAergic interneuron development and function is modulated by the Tsc1 gene.
      ).
      Interneuronal input/output function can also be compromised. Deficiency of Shank1, highly expressed in PV cells, suppresses excitatory synaptic input and GABAergic output of PV interneurons, increasing E/I ratio in target neurons (
      • Mao W.
      • Watanabe T.
      • Cho S.
      • Frost J.L.
      • Truong T.
      • Zhao X.
      • Futai K.
      Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons.
      ). Mice lacking PV (Pvalb) show altered short-term plasticity of excitatory cortical inputs to PV interneurons and social deficits and repetitive behavior (
      • Wohr M.
      • Orduz D.
      • Gregory P.
      • Moreno H.
      • Khan U.
      • Vorckel K.J.
      • et al.
      Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities.
      ). Cntnap2 mice show suppressed perisomatic evoked IPSC input-output curve (
      • Jurgensen S.
      • Castillo P.E.
      Selective dysregulation of hippocampal inhibition in the mouse lacking autism candidate gene CNTNAP2.
      ), in addition to reduced PV cell counts, defective neuronal migration, and epilepsy (
      • Penagarikano O.
      • Abrahams B.S.
      • Herman E.I.
      • Winden K.D.
      • Gdalyahu A.
      • Dong H.
      • et al.
      Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits.
      ). However, CNTNAP2 also regulates dendrite and spine development and AMPAR trafficking in pyramidal neurons (
      • Gdalyahu A.
      • Lazaro M.
      • Penagarikano O.
      • Golshani P.
      • Trachtenberg J.T.
      • Geschwind D.H.
      The autism related protein contactin-associated protein-like 2 (CNTNAP2) stabilizes new spines: An in vivo mouse study.
      ,
      • Varea O.
      • Martin-de-Saavedra M.D.
      • Kopeikina K.J.
      • Schurmann B.
      • Fleming H.J.
      • Fawcett-Patel J.M.
      • et al.
      Synaptic abnormalities and cytoplasmic glutamate receptor aggregates in contactin associated protein-like 2/Caspr2 knockout neurons.
      ,
      • Anderson G.R.
      • Galfin T.
      • Xu W.
      • Aoto J.
      • Malenka R.C.
      • Sudhof T.C.
      Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development.
      ), suggesting that it regulates both excitatory and inhibitory synapses.
      Impaired interneuronal firing would suppress GABAergic signaling. Mice heterozygous for the voltage-gated sodium channel Nav1.1 (Scn1a+/-), a model for Dravet syndrome characterized by intractable seizure and social and cognitive deficits, show limited action potential firing and GABAergic output, together with social and spatial and fear memory deficits (
      • Ito S.
      • Ogiwara I.
      • Yamada K.
      • Miyamoto H.
      • Hensch T.K.
      • Osawa M.
      • Yamakawa K.
      Mouse with Nav1.1 haploinsufficiency, a model for Dravet syndrome, exhibits lowered sociability and learning impairment.
      ,
      • Han S.
      • Tai C.
      • Westenbroek R.E.
      • Yu F.H.
      • Cheah C.S.
      • Potter G.B.
      • et al.
      Autistic-like behaviour in Scn1a+/- mice and rescue by enhanced GABA-mediated neurotransmission.
      ). These features are recapitulated by Nav1.1 knockout restricted to forebrain GABAergic interneurons (Dlx1/2-Cre;Scn1a+/–) and are rescued by the GABAA receptor agonist clonazepam (
      • Han S.
      • Tai C.
      • Westenbroek R.E.
      • Yu F.H.
      • Cheah C.S.
      • Potter G.B.
      • et al.
      Autistic-like behaviour in Scn1a+/- mice and rescue by enhanced GABA-mediated neurotransmission.
      ). Similarly, BTBR mice show reduced hippocampal spontaneous IPSC frequency and social and cognitive deficits responsive to clonazepam (
      • Han S.
      • Tai C.
      • Jones C.J.
      • Scheuer T.
      • Catterall W.A.
      Enhancement of inhibitory neurotransmission by GABAA receptors having α2,3-subunits ameliorates behavioral deficits in a mouse model of autism.
      ), similar to the improved social avoidance observed in diazepam-treated BTBR mice (
      • Defensor E.B.
      • Pearson B.L.
      • Pobbe R.L.
      • Bolivar V.J.
      • Blanchard D.C.
      • Blanchard R.J.
      A novel social proximity test suggests patterns of social avoidance and gaze aversion-like behavior in BTBR T+ tf/J mice.
      ).
      Limited nerve terminal development and function would affect GABAergic signaling. Mice lacking Mecp2 in GABAergic interneurons (Viaat-Cre;Mecp2) show reduced quantal GABA content and messenger RNA levels for GABA-synthesizing GAD65 and GAD67 (
      • Chao H.T.
      • Chen H.
      • Samaco R.C.
      • Xue M.
      • Chahrour M.
      • Yoo J.
      • et al.
      Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.
      ). Mice lacking the synaptic vesicle protein synapsin I (SynI), implicated in ASD and epilepsy, show epileptic propensity, and neurons from these mice re-expressing a disease-related mutant SynI display reduced readily releasable pool of GABA-containing vesicles and stronger short-term depression (
      • Lignani G.
      • Raimondi A.
      • Ferrea E.
      • Rocchi A.
      • Paonessa F.
      • Cesca F.
      • et al.
      Epileptogenic Q555X SYN1 mutant triggers imbalances in release dynamics and short-term plasticity.
      ), which may involve abnormally activated eEF2K/eEF2 signaling (
      • Heise C.
      • Taha E.
      • Murru L.
      • Ponzoni L.
      • Cattaneo A.
      • Guarnieri F.C.
      • et al.
      eEF2K/eEF2 Pathway controls the excitation/inhibition balance and susceptibility to epileptic seizures [published online ahead of print Mar 21].
      ). Conditional deletion of ErbB4 in PV neurons causes reduced neuregulin-dependent GABA release in the prefrontal cortex and cognitive deficits that are rescued by diazepam (
      • Wen L.
      • Lu Y.S.
      • Zhu X.H.
      • Li X.M.
      • Woo R.S.
      • Chen Y.J.
      • et al.
      Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons.
      ), results in line with the increased seizure susceptibility observed in these mice (
      • Tan G.H.
      • Liu Y.Y.
      • Hu X.L.
      • Yin D.M.
      • Mei L.
      • Xiong Z.Q.
      Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons.
      ,
      • Li K.X.
      • Lu Y.M.
      • Xu Z.H.
      • Zhang J.
      • Zhu J.M.
      • Zhang J.M.
      • et al.
      Neuregulin 1 regulates excitability of fast-spiking neurons through Kv1.1 and acts in epilepsy.
      ). Ube3a mice show reduced GABAergic output in the visual cortex due to reduced defective presynaptic vesicle cycling prominent at P80 but not at P25 (
      • Wallace M.L.
      • Burette A.C.
      • Weinberg R.J.
      • Philpot B.D.
      Maternal loss of Ube3a produces an excitatory/inhibitory imbalance through neuron type-specific synaptic defects.
      ).
      Dysfunctional interneurons would fail to properly develop inhibitory synapses with target neurons. A deficiency of CNTNAP4, highly expressed in developing interneurons, in mice causes reduced PV interneuronal output through limited inhibitory synapse maturation, as evidenced by widened synaptic cleft gap, and enhanced startle responses rescued by the GABAA receptor agonist Indiplon (
      • Karayannis T.
      • Au E.
      • Patel J.C.
      • Kruglikov I.
      • Markx S.
      • Delorme R.
      • et al.
      Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission.
      ). In addition, mice lacking the oxytocin receptor (Oxtr) show decreased hippocampal inhibitory presynaptic density and increased seizure susceptibility, together with social and learning defects responsive to prosocial neuropeptides, oxytocin and vasopressin (
      • Sala M.
      • Braida D.
      • Lentini D.
      • Busnelli M.
      • Bulgheroni E.
      • Capurro V.
      • et al.
      Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: A neurobehavioral model of autism.
      ), although rescue mechanisms downstream of receptor activation remain unclear.

      Glial Cells

      Glial cell dysfunctions can disturb neuronal E/I balance. Supporting astrocytic contribution, astrocyte-specific deletion of GLT1 (Glast-CreERT2;Glt1), a glutamate transporter expressed in neurons and glia, induces increased excitatory transmission, seizure susceptibility, and repetitive behavior that is responsive to memantine (
      • Aida T.
      • Yoshida J.
      • Nomura M.
      • Tanimura A.
      • Iino Y.
      • Soma M.
      • et al.
      Astroglial glutamate transporter deficiency increases synaptic excitability and leads to pathological repetitive behaviors in mice.
      ). Mice lacking PTEN in astrocytes (Gfap-Cre;Pten) show abnormal excitatory synapse structure and reduced excitatory transmission and LTP (
      • Fraser M.M.
      • Bayazitov I.T.
      • Zakharenko S.S.
      • Baker S.J.
      Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities.
      ). In addition, astrocyte-specific re-expression of Mecp2 in Mecp2-deficient mice restores disease-related phenotypes, including premature lethality, abnormal respiration, hypoactivity, and reduced dendritic complexity [a noncell-autonomous effect (
      • Lioy D.T.
      • Garg S.K.
      • Monaghan C.E.
      • Raber J.
      • Foust K.D.
      • Kaspar B.K.
      • et al.
      A role for glia in the progression of Rett’s syndrome.
      )]. Nonastrocytic glial cells such as microglia and oligodendrocytes are also important. For instance, microglia-specific re-expression of MeCP2 in Mecp2 mice (Lysm-Cre;Mecp2lox-stop/y) ameliorates disease-related phenotypes (
      • Derecki N.C.
      • Cronk J.C.
      • Lu Z.
      • Xu E.
      • Abbott S.B.
      • Guyenet P.G.
      • Kipnis J.
      Wild-type microglia arrest pathology in a mouse model of Rett syndrome.
      ).

      Intrinsic Neuronal Excitability

      Neuronal excitability acts together with synaptic E/I balance to modulate neuronal firing. Rats prenatally exposed to VPA show reduced neuronal excitability in addition to enhanced NMDAR function and NMDAR-dependent LTP (
      • Rinaldi T.
      • Kulangara K.
      • Antoniello K.
      • Markram H.
      Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid.
      ,
      • Walcott E.C.
      • Higgins E.A.
      • Desai N.S.
      Synaptic and intrinsic balancing during postnatal development in rat pups exposed to valproic acid in utero.
      ). Interestingly, both enhanced NMDAR function and reduced excitability peak around birth and are progressively and concurrently corrected to normal levels within ~3 weeks (
      • Walcott E.C.
      • Higgins E.A.
      • Desai N.S.
      Synaptic and intrinsic balancing during postnatal development in rat pups exposed to valproic acid in utero.
      ), suggesting that neuronal excitability compensates for NMDAR function. Similarly, enhanced excitatory transmission and reduced excitability are observed in brain-specific Foxp1-deficient mice (Nestin-Cre;Foxp1), which display social impairments and repetitive behavior (
      • Bacon C.
      • Schneider M.
      • Le Magueresse C.
      • Froehlich H.
      • Sticht C.
      • Gluch C.
      • et al.
      Brain-specific Foxp1 deletion impairs neuronal development and causes autistic-like behaviour.
      ).
      An important regulator of intrinsic excitability is dendritic ion channels. Fmr1 mice show reduced expression and impaired function of dendritic h- and BKCa (big potassium) channels in cortical pyramidal neurons, associated with dendritic hyperexcitability and sensory hypersensitivity that are corrected by the BKCa channel activator, BMS-191011 (
      • Zhang Y.
      • Bonnan A.
      • Bony G.
      • Ferezou I.
      • Pietropaolo S.
      • Ginger M.
      • et al.
      Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1(-/y) mice.
      ). Recently, reduced h-channel function has been reported in Shank3-deficient mouse and human neurons (
      • Yi F.
      • Danko T.
      • Botelho S.C.
      • Patzke C.
      • Pak C.
      • Wernig M.
      • Sudhof T.C.
      Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons.
      ).
      Some intrinsic excitability mechanisms seem to overlap with ASD mechanisms. Neuregulin-ErbB4 signaling, an aforementioned regulator of interneuronal GABAergic output, increases the intrinsic excitability of PV interneurons by inhibiting the voltage-dependent potassium channel, KV1.1 (
      • Tan G.H.
      • Liu Y.Y.
      • Hu X.L.
      • Yin D.M.
      • Mei L.
      • Xiong Z.Q.
      Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons.
      ,
      • Li K.X.
      • Lu Y.M.
      • Xu Z.H.
      • Zhang J.
      • Zhu J.M.
      • Zhang J.M.
      • et al.
      Neuregulin 1 regulates excitability of fast-spiking neurons through Kv1.1 and acts in epilepsy.
      ).

      Homeostatic Synaptic Plasticity

      Homeostatic plasticity works at the level of neuronal synapses in addition to intrinsic neuronal excitability (
      • Turrigiano G.
      Homeostatic synaptic plasticity: Local and global mechanisms for stabilizing neuronal function.
      ). Mecp2 mice show impaired upward excitatory synaptic scaling in visual cortical neurons (
      • Blackman M.P.
      • Djukic B.
      • Nelson S.B.
      • Turrigiano G.G.
      A critical and cell-autonomous role for MeCP2 in synaptic scaling up.
      ) and downward scaling in hippocampal neurons (
      • Qiu Z.
      • Sylwestrak E.L.
      • Lieberman D.N.
      • Zhang Y.
      • Liu X.Y.
      • Ghosh A.
      The Rett syndrome protein MeCP2 regulates synaptic scaling.
      ,
      • Zhong X.
      • Li H.
      • Chang Q.
      MeCP2 phosphorylation is required for modulating synaptic scaling through mGluR5.
      ). Fmr1 mice show blocked upward excitatory synaptic scaling in the hippocampus (
      • Soden M.E.
      • Chen L.
      Fragile X protein FMRP is required for homeostatic plasticity and regulation of synaptic strength by retinoic acid.
      ), and upward inhibitory synaptic scaling in the amygdala (
      • Vislay R.L.
      • Martin B.S.
      • Olmos-Serrano J.L.
      • Kratovac S.
      • Nelson D.L.
      • Corbin J.G.
      • Huntsman M.M.
      Homeostatic responses fail to correct defective amygdala inhibitory circuit maturation in fragile X syndrome.
      ). In addition, GKAP/DLGAP1/SAPAP1, a postsynaptic scaffold implicated in ASD, regulates hippocampal excitatory synaptic scaling in a bidirectional manner (
      • Shin S.M.
      • Zhang N.
      • Hansen J.
      • Gerges N.Z.
      • Pak D.T.
      • Sheng M.
      • Lee S.H.
      GKAP orchestrates activity-dependent postsynaptic protein remodeling and homeostatic scaling.
      ).

      Temporal E/I Regulation

      Synaptic and circuit E/I balances are established and fine-tuned during brain development and through sensory experience. In immature brains, GABA acts as an excitatory neurotransmitter because of the prevailing high intracellular chloride concentration ([Cl]i) (
      • Ben-Ari Y.
      Is birth a critical period in the pathogenesis of autism spectrum disorders?.
      ). The high [Cl]i built up by the chloride importer, NKCC1, is gradually diminished by the chloride exporter KCC2, shifting GABA action from depolarization to hyperpolarization. The depolarizing GABA action is transiently inhibited during birth by maternal oxytocin, but is abnormally suppressed in Fmr1 mice and VPA rats (
      • Tyzio R.
      • Nardou R.
      • Ferrari D.C.
      • Tsintsadze T.
      • Shahrokhi A.
      • Eftekhari S.
      • et al.
      Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring.
      ). Elegantly, maternal pretreatment with the NKCC1 blocker bumetanide before delivery normalizes disease phenotypes in both models (P15) (
      • Tyzio R.
      • Nardou R.
      • Ferrari D.C.
      • Tsintsadze T.
      • Shahrokhi A.
      • Eftekhari S.
      • et al.
      Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring.
      ). In addition, bumetanide rescues impaired ultrasonic vocalization in pups (P4) (
      • Tyzio R.
      • Nardou R.
      • Ferrari D.C.
      • Tsintsadze T.
      • Shahrokhi A.
      • Eftekhari S.
      • et al.
      Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring.
      ) and social deficits in adult offspring (2.5/4.5 months) (
      • Eftekhari S.
      • Shahrokhi A.
      • Tsintsadze V.
      • Nardou R.
      • Brouchoud C.
      • Conesa M.
      • et al.
      Response to Comment on “Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring.”.
      ), suggesting that an early E/I imbalance has long-lasting effects (
      • Ben-Ari Y.
      Is birth a critical period in the pathogenesis of autism spectrum disorders?.
      ).
      Another example of temporal E/I imbalance is Syngap1 heterozygous mice. In these mice, induction of a Syngap1 mutation in adult mice (>8 weeks) does not alter synaptic function, but restoration of Syngap1 expression in newborn Syngap1-mutant mice at P1 improves cognitive and memory functions (
      • Clement J.P.
      • Aceti M.
      • Creson T.K.
      • Ozkan E.D.
      • Shi Y.
      • Reish N.J.
      • et al.
      Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses.
      ,
      • Aceti M.
      • Creson T.K.
      • Vaissiere T.
      • Rojas C.
      • Huang W.C.
      • Wang Y.X.
      • et al.
      Syngap1 haploinsufficiency damages a postnatal critical period of pyramidal cell structural maturation linked to cortical circuit assembly.
      ), suggesting again that an early E/I imbalance has long-lasting effects.
      However, there are cases in which delayed restoration rescues abnormal phenotypes. For instance, re-expression of Nlgn-3 in Nlgn3-deficient mice at P30 restores mGluR1α expression and ectopic synapse formation in the cerebellum (
      • Baudouin S.J.
      • Gaudias J.
      • Gerharz S.
      • Hatstatt L.
      • Zhou K.
      • Punnakkal P.
      • et al.
      Shared synaptic pathophysiology in syndromic and nonsyndromic rodent models of autism.
      ). In addition, re-expression of Mecp2 in adult Mecp2 mice (~12–17 weeks) restores LTP and disease-related phenotypes (
      • Guy J.
      • Gan J.
      • Selfridge J.
      • Cobb S.
      • Bird A.
      Reversal of neurological defects in a mouse model of Rett syndrome.
      ), and, conversely, genetic or antisense-mediated Mecp2 suppression in adult Mecp2-overexpressing mice (~7–8 to 11–12 weeks) rescues major phenotypes (
      • Sztainberg Y.
      • Chen H.M.
      • Swann J.W.
      • Hao S.
      • Tang B.
      • Wu Z.
      • et al.
      Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides.
      ). Moreover, re-expression of maternal Ube3a in Ube3a mice at 3, 6, and 12 weeks differentially rescue disease-related phenotypes (
      • Silva-Santos S.
      • van Woerden G.M.
      • Bruinsma C.F.
      • Mientjes E.
      • Jolfaei M.A.
      • Distel B.
      • et al.
      Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model.
      ), collectively suggesting that ASD-related mutations have distinct time course of phenotype development and reversibility.

      Perspectives

      To minimize the difficulty of differentiating primary and secondary changes in animal models of ASD, we have sought in this review to highlight studies that attempted pharmacologic rescue and conditional knockout/rescue experiments.
      However, care should be taken in interpreting these results because the observed rescues may merely represent apparent phenotypic alleviation rather than fundamental correction of key pathogenic mechanisms. In addition, the phenotypes observed in conditional knockout mice, although clearer than those from conventional knockouts, may not represent the consequences of the intricate interplay among different cell types that occurs in real pathological conditions.
      Adding to this complexity, a substantial portion of the primary pathological changes likely occurs during embryonic or early postnatal periods and exerts long-lasting effects. Therefore, the rescue results obtained using adult animals may not necessarily provide insights into early and primary changes. We thus need to identify key mechanisms that contribute to the initiation, development, and maintenance of autistic-like phenotypes along the temporal axis. These efforts would need to involve genetic manipulations and pharmacologic interventions at different time points, and observation of their short- and long-term consequences.
      Pathogenic mechanisms underlying E/I imbalance in ASDs are more complex than might have been expected. Recent studies have even begun to show that the same gene mutation leads to distinct synaptic E/I imbalances in different synapses, cell types, and brain regions at different time points. Collectively, these findings highlight the importance of pursuing detailed and integrative analyses of E/I imbalances in future studies of animal models of ASD.

      Acknowledgments and Disclosures

      This work was supported by the Institute for Basic Science Grant No. IBS-R002-D1 (to EK). All authors report no biomedical financial interests or potential conflicts of interest.

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