Advertisement
Archival Report| Volume 81, ISSUE 3, P193-202, February 01, 2017

Sociability Deficits and Altered Amygdala Circuits in Mice Lacking Pcdh10, an Autism Associated Gene

      Abstract

      Background

      Behavioral symptoms in individuals with autism spectrum disorder (ASD) have been attributed to abnormal neuronal connectivity, but the molecular bases of these behavioral and brain phenotypes are largely unknown. Human genetic studies have implicated PCDH10, a member of the δ2 subfamily of nonclustered protocadherin genes, in ASD. PCDH10 expression is enriched in the basolateral amygdala, a brain region implicated in the social deficits of ASD. Previous reports indicate that Pcdh10 plays a role in axon outgrowth and glutamatergic synapse elimination, but its roles in social behaviors and amygdala neuronal connectivity are unknown. We hypothesized that haploinsufficiency of Pcdh10 would reduce social approach behavior and alter the structure and function of amygdala circuits.

      Methods

      Mice lacking one copy of Pcdh10 (Pcdh10+/–) and wild-type littermates were assessed for social approach and other behaviors. The lateral/basolateral amygdala was assessed for dendritic spine number and morphology, and amygdala circuit function was studied using voltage-sensitive dye imaging. Expression of Pcdh10 and N-methyl-D-aspartate receptor (NMDAR) subunits was assessed in postsynaptic density fractions of the amygdala.

      Results

      Male Pcdh10+/– mice have reduced social approach behavior, as well as impaired gamma synchronization, abnormal spine morphology, and reduced levels of NMDAR subunits in the amygdala. Social approach deficits in Pcdh10+/– male mice were rescued with acute treatment with the NMDAR partial agonist d-cycloserine.

      Conclusions

      Our studies reveal that male Pcdh10+/– mice have synaptic and behavioral deficits, and establish Pcdh10+/– mice as a novel genetic model for investigating neural circuitry and behavioral changes relevant to ASD.

      Keywords

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

      Purchase one-time access:

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

      Subscribe:

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

      References

        • Chevallier C.
        • Kohls G.
        • Troiani V.
        • Brodkin E.S.
        • Schultz R.T.
        The social motivation theory of autism.
        Trends Cogn Sci. 2012; 16: 231-239
        • Werling D.M.
        • Geschwind D.H.
        Sex differences in autism spectrum disorders.
        Curr Opin Neurol. 2013; 26: 146-153
        • Hartley S.L.
        • Sikora D.M.
        Sex differences in autism spectrum disorder: An examination of developmental functioning, autistic symptoms, and coexisting behavior problems in toddlers.
        J Autism Dev Disord. 2009; 39: 1715-1722
        • Gilman S.R.
        • Iossifov I.
        • Levy D.
        • Ronemus M.
        • Wigler M.
        • Vitkup D.
        Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses.
        Neuron. 2011; 70: 898-907
        • Irwin S.A.
        • Patel B.
        • Idupulapati M.
        • Harris J.B.
        • Crisostomo R.A.
        • Larsen B.P.
        • et al.
        Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: A quantitative examination.
        Am J Med Genet. 2001; 98: 161-167
        • Wolff J.J.
        • Gu H.
        • Gerig G.
        • Elison J.T.
        • Styner M.
        • Gouttard S.
        • et al.
        Differences in white matter fiber tract development present from 6 to 24 months in infants with autism.
        Am J Psychiatry. 2012; 169: 589-600
        • Hutsler J.J.
        • Zhang H.
        Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders.
        Brain Res. 2010; 1309: 83-94
        • Toro R.
        • Konyukh M.
        • Delorme R.
        • Leblond C.
        • Chaste P.
        • Fauchereau F.
        • et al.
        Key role for gene dosage and synaptic homeostasis in autism spectrum disorders.
        Trends Genet. 2010; 26: 363-372
        • Morrow E.M.
        • Yoo S.-Y.
        • Flavell S.W.
        • Kim T.-K.
        • Lin Y.
        • Hill R.S.
        • et al.
        Identifying autism loci and genes by tracing recent shared ancestry.
        Science. 2008; 321: 218-223
        • De Rubeis S.
        • He X.
        • Goldberg A.P.
        • Poultney C.S.
        • Samocha K.
        • Ercument Cicek A.
        • et al.
        Synaptic, transcriptional and chromatin genes disrupted in autism.
        Nature. 2014; 515: 209-215
        • O’Roak B.J.
        • Vives L.
        • Girirajan S.
        • Karakoc E.
        • Krumm N.
        • Coe B.P.
        • et al.
        Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.
        Nature. 2012; 485: 246-250
        • Kim S.Y.
        • Yasuda S.
        • Tanaka H.
        • Yamagata K.
        • Kim H.
        Non-clustered protocadherin.
        Cell Adh Migr. 2011; 5: 97-105
        • Bucan M.
        • Abrahams B.S.
        • Wang K.
        • Glessner J.T.
        • Herman E.I.
        • Sonnenblick L.I.
        • et al.
        Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes.
        PLoS Genet. 2009; 5: e1000536
        • Hirano S.
        • Yan Q.
        • Suzuki S.T.
        Expression of a novel protocadherin, OL-protocadherin, in a subset of functional systems of the developing mouse brain.
        J Neurosci. 1999; 19: 995-1005
        • Aoki E.
        • Kimura R.
        • Suzuki S.T.
        • Hirano S.
        Distribution of OL-protocadherin protein in correlation with specific neural compartments and local circuits in the postnatal mouse brain.
        Neuroscience. 2003; 117: 593-614
        • Kim J.E.
        • Lyoo I.K.
        • Estes A.M.
        • Renshaw P.F.
        • Shaw D.W.
        • Friedman S.D.
        • et al.
        Laterobasal amygdalar enlargement in 6- to 7-year-old children with autism spectrum disorder.
        Arch Gen Psychiatry. 2010; 67: 1187-1197
        • Tsai N.-P.
        • Wilkerson J.R.
        • Guo W.
        • Maksimova M.
        • DeMartino G.N.
        • Cowan C.W.
        • et al.
        Multiple autism-linked genes mediate synapse elimination via proteasomal degradation of a synaptic scaffold PSD-95.
        Cell. 2012; 151: 1581-1594
        • Dictenberg J.B.
        • Swanger S.
        • Antar L.N.
        • Singer R.H.
        • Bassell G.J.
        A direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome.
        Dev Cell. 2008; 14: 926-939
        • Nakao S.
        • Platek A.
        • Hirano S.
        • Takeichi M.
        Contact-dependent promotion of cell migration by the OL-protocadherin-Nap1 interaction.
        J Cell Biol. 2008; 182: 395-410
        • Pilpel Y.
        • Segal M.
        Rapid WAVE dynamics in dendritic spines of cultured hippocampal neurons is mediated by actin polymerization.
        J Neurochem. 2005; 95: 1401-1410
        • DeRubeis S.
        • Pasciuto E.
        • Li K.
        • Fernández E.
        • DiMarino D.
        • Buzzi A.
        • et al.
        CYFIP1 coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation.
        Neuron. 2013; 79: 1169-1182
        • Uemura M.
        • Nakao S.
        • Suzuki S.T.
        • Takeichi M.
        • Hirano S.
        OL-Protocadherin is essential for growth of striatal axons and thalamocortical projections.
        Nat Neurosci. 2007; 10 (1151–119)
        • Fairless A.H.
        • Shah R.Y.
        • Guthrie A.J.
        • Li H.
        • Brodkin E.S.
        Deconstructing sociability, an autism-relevant phenotype, in mouse models.
        Anat Rec. 2011; 294: 1713-1725
        • Ehrlichman R.S.
        • Luminais S.N.
        • White S.L.
        • Rudnick N.D.
        • Ma N.
        • Dow H.C.
        • et al.
        Neuregulin 1 transgenic mice display reduced mismatch negativity, contextual fear conditioning and social interactions.
        Brain Res. 2009; 1294: 116-127
        • Tarantino L.M.
        • Gould T.J.
        • Druhan J.P.
        • Bucan M.
        Behavior and mutagenesis screens: The importance of baseline analysis of inbred strains.
        Mamm Genome. 2000; 11: 555-564
        • Yang M.
        • Crawley J.N.
        Simple behavioral assessment of mouse olfaction.
        Curr Protoc Neurosci. 2009; 8: 8.24
        • Peça 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.
        Nature. 2011; 472: 437-442
        • Tabuchi K.
        • Blundell J.
        • Etherton M.R.
        • Hammer R.E.
        • Liu X.
        • Powell C.M.
        • et al.
        A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice.
        Science. 2007; 318: 71-76
        • Kwon C.H.
        • Luikart B.W.
        • Powell C.M.
        • Zhou J.
        • Matheny S.A.
        • Zhang W.
        • et al.
        Pten regulates neuronal arborization and social interaction in mice.
        Neuron. 2006; 50: 377-388
        • Pietropaolo S.
        • Guilleminot A.
        • Martin B.
        • D’Amato F.R.
        • Crusio W.E.
        Genetic-background modulation of core and variable autistic-like symptoms in Fmr1 knock-out mice.
        PLoS One. 2011; 6: e17073
        • 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.
        Biol Psychiatry. 2011; 69: 875-882
        • Nakatani J.
        • Tamada K.
        • Hatanaka F.
        • Ise S.
        • Ohta H.
        • Inoue K.
        • et al.
        Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism.
        Cell. 2009; 137: 1235-1246
        • Hamilton S.M.
        • Spencer C.M.
        • Harrison W.R.
        • Yuva-Paylor L.A.
        • Graham D.F.
        • Daza R.A.M.
        • et al.
        Multiple autism-like behaviors in a novel transgenic mouse model.
        Behav Brain Res. 2011; 218: 29-41
        • Bidinosti M.
        • Botta P.
        • Kruttner S.
        • Proenca C.C.
        • Stoehr N.
        • Bernhard M.
        • et al.
        CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency.
        Science. 2016; 351: 1199-1203
        • Branchi I.
        • Santucci D.
        • Alleva E.
        Ultrasonic vocalisation emitted by infant rodents: A tool for assessment of neurobehavioural development.
        Behav Brain Res. 2001; 125: 49-56
        • Hering H.
        • Sheng M.
        Dendritic spines: structure, dynamics and regulation.
        Nat Rev Neurosci. 2001; 2: 880-888
        • Yuste R.
        • Bonhoeffer T.
        Genesis of dendritic spines: insights from ultrastructural and imaging studies.
        Nat Rev Neurosci. 2004; 5: 24-34
        • Carlson G.C.
        • Coulter D.A.
        In vitro functional imaging in brain slices using fast voltage-sensitive dye imaging combined with whole-cell patch recording.
        Nat Protoc. 2008; 3: 249-255
        • Oostenveld R.
        • Fries P.
        • Maris E.
        • Schoffelen J.M.
        FieldTrip: Open source software for advanced analysis of MEG, EEG, and invasive electrophysiological data.
        Comput Intell Neurosci. 2011; 2011: 156869
        • Gandal M.J.
        • Edgar J.C.
        • Ehrlichman R.S.
        • Mehta M.
        • Roberts T.P.L.
        • Siegel S.J.
        Validating γ oscillations and delayed auditory responses as translational biomarkers of autism.
        Biol Psychiatry. 2010; 68: 1100-1106
        • Hahn C.G.
        • Banerjee A.
        • MacDonald M.L.
        • Cho D.S.
        • Kamins J.
        • Nie Z.
        • et al.
        The post-synaptic density of human postmortem brain tissues: An experimental study paradigm for neuropsychiatric illnesses.
        PLoS One. 2009; 4: e5251
        • Banerjee a
        • Wang H.-Y.
        • Borgmann-Winter K.E.
        • MacDonald M.L.
        • Kaprielian H.
        • Stucky A.
        • et al.
        Src kinase as a mediator of convergent molecular abnormalities leading to NMDAR hypoactivity in schizophrenia.
        Mol Psychiatry. 2014; 20: 1091-1100
        • Fairless A.H.
        • Dow H.C.
        • Kreibich A.S.
        • Torre M.
        • Kuruvilla M.
        • Gordon E.
        • et al.
        Sociability and brain development in BALB/cJ and C57BL/6J mice.
        Behav Brain Res. 2012; 228: 299-310
        • Lee E.-J.
        • Choi S.Y.
        • Kim E.
        NMDA receptor dysfunction in autism spectrum disorders.
        Curr Opin Pharmacol. 2015; 20: 8-13
        • Rung J.P.
        • Carlsson A.
        • Markinhuhta K.R.
        • Carlsson M.L.
        (+)-MK-801 induced social withdrawal in rats; A model for negative symptoms of schizophrenia.
        Prog Neuropsychopharmacol Biol Psychiatry. 2005; 29: 827-832
        • Wright B.
        • Alderson-Day B.
        • Prendergast G.
        • Bennett S.
        • Jordan J.
        • Whitton C.
        • et al.
        Gamma activation in young people with autism spectrum disorders and typically-developing controls when viewing emotions on faces.
        PLoS One. 2012; 7: e41326
        • Verbeke G.
        • Molenberghs G.
        Linear Mixed Models for Longitudinal Data. Springer Series in Statistics.
        Springer, New York2000
        • Gibbons R.D.
        • Hedeker D.
        • Elkin I.
        • Waternaux C.
        • Kraemer H.C.
        • Greenhouse J.B.
        • et al.
        Some conceptual and statistical issues in analysis of longitudinal psychiatric data: Application to the nimh treatment of depression collaborative research program dataset.
        Arch Gen Psychiatry. 1993; 50: 739-750
        • Fairless A.H.
        • Katz J.M.
        • Vijayvargiya N.
        • Dow H.C.
        • Kreibich A.S.
        • Berrettini W.H.
        • et al.
        Development of home cage social behaviors in BALB/cJ vs. C57BL/6J mice.
        Behav Brain Res. 2013; 237: 338-347
        • Sankoorikal G.M.
        • Kaercher K.A.
        • Boon C.J.
        • Lee J.K.
        • Brodkin E.S.
        A mouse model system for genetic analysis of sociability: C57BL/6J versus BALB/cJ inbred mouse strains.
        Biol Psychiatry. 2006; 59: 415-423
        • Scattoni M.L.
        • Gandhy S.U.
        • Ricceri L.
        • Crawley J.N.
        Unusual repertoire of vocalizations in the BTBR T+tf/J mouse model of autism.
        PLoS One. 2008; 3: e3067
        • Wilson T.W.
        • Rojas D.C.
        • Reite M.L.
        • Teale P.D.
        • Rogers S.J.
        Children and adolescents with autism exhibit reduced MEG steady-state gamma responses.
        Biol Psychiatry. 2007; 62: 192-197
        • Das P.
        • Kemp A.H.
        • Flynn G.
        • Harris A.W.F.
        • Liddell B.J.
        • Whitford T.J.
        • et al.
        Functional disconnections in the direct and indirect amygdala pathways for fear processing in schizophrenia.
        Schizophr Res. 2007; 90: 284-294
        • Supekar K.
        • Uddin L.Q.
        • Khouzam A.
        • Phillips J.
        • Gaillard W.D.
        • Kenworthy L.E.
        • et al.
        Brain Hyperconnectivity in children with autism and its links to social deficits.
        Cell Rep. 2013; 5: 738-747
        • Felix-Ortiz A.C.
        • Beyeler A.
        • Seo C.
        • Leppla C.A.
        • Wildes C.P.
        • Tye K.M.
        BLA to vHPC inputs modulate anxiety-related behaviors.
        Neuron. 2013; 79: 658-664
        • Ferguson J.N.
        • Aldag J.M.
        • Insel T.R.
        • Young L.J.
        Oxytocin in the medial amygdala is essential for social recognition in the mouse.
        J Neurosci. 2001; 21: 8278-8285
        • Ziv N.E.
        • Smith S.J.
        Evidence for a role of dendritic filopodia in synaptogenesis and spine formation.
        Neuron. 1996; 17: 91-102
        • Gandal M.J.
        • Sisti J.
        • Klook K.
        • Ortinski P.I.
        • Leitman V.
        • Liang Y.
        • et al.
        GABAB-mediated rescue of altered excitatory–inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction.
        Translational Psychiatry. 2012; 2: e142
        • 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.
        Nature. 2012; 486: 261-265
        • Posey D.J.
        • Kem D.L.
        • Swiezy N.B.
        • Sweeten T.L.
        • Wiegand R.E.
        • McDougle C.J.
        A pilot study of D-cycloserine in subjects with autistic disorder.
        Am J Psychiatry. 2004; 161: 2115-2117
        • 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.
        Brain Res Bull. 2013; 96: 62-70
        • 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.
        J Neurosci. 2010; 30: 2115-2129
        • Mandy W.P.L.
        • Skuse D.H.
        Research review: What is the association between the social-communication element of autism and repetitive interests, behaviours and activities?.
        J Child Psychol Psychiatry. 2008; 49: 795-808
        • Kleinhans N.M.
        • Richards T.
        • Weaver K.
        • Johnson L.C.
        • Greenson J.
        • Dawson G.
        • et al.
        Association between amygdala response to emotional faces and social anxiety in autism spectrum disorders.
        Neuropsychologia. 2010; 48: 3665-3670
        • Williams L.M.
        • Whitford T.J.
        • Nagy M.
        • Flynn G.
        • Harris A.W.F.
        • Silverstein S.M.
        • et al.
        Emotion-elicited gamma synchrony in patients with first-episode schizophrenia: A neural correlate of social cognition outcomes.
        J Psychiatry Neurosci. 2009; 34: 303-313
        • Irwin S.A.
        • Galvez R.
        • Greenough W.T.
        Dendritic spine structural anomalies in fragile-X mental retardation syndrome.
        Cereb Cortex. 2000; 10: 1038-1044
        • Petrak L.J.
        • Harris K.M.
        • Kirov S.A.
        Synaptogenesis on mature hippocampal dendrites occurs via filopodia and immature spines during blocked synaptic transmission.
        J Comp Neurol. 2005; 484: 183-190
        • Lin S.Y.
        • Constantine-Paton M.
        Suppression of sprouting: An early function of NMDA receptors in the absence of AMPA/kainate receptor activity.
        J Neurosci. 1998; 18: 3725-3737
        • Chen Y.
        • Wang Y.
        • Ertürk A.
        • Kallop D.
        • Jiang Z.
        • Weimer R.M.
        • et al.
        Activity-induced Nr4a1 regulates spine density and distribution pattern of excitatory synapses in pyramidal neurons.
        Neuron. 2014; 83: 431-443
        • Comery T.A.
        • Harris J.B.
        • Willems P.J.
        • Oostra B.A.
        • Irwin S.A.
        • Weiler I.J.
        • et al.
        Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits.
        Proc Natl Acad Sci U S A. 1997; 94: 5401-5404
        • Harris K.M.
        • Stevens J.K.
        Dendritic spines of CA 1 pyramidal cells in the rat hippocampus: serial electron microscopy with reference to their biophysical characteristics.
        J Neurosci. 1989; 9: 2982-2997
        • Lazarewicz M.T.
        • Ehrlichman R.S.
        • Maxwell C.R.
        • Gandal M.J.
        • Finkel L.H.
        • Siegel S.J.
        Ketamine modulates theta and gamma oscillations.
        J Cogn Neurosci. 2010; 22: 1452-1464
        • Schmidt A.
        • Kometer M.
        • Bachmann R.
        • Seifritz E.
        • Vollenweider F.
        The NMDA antagonist ketamine and the 5-HT agonist psilocybin produce dissociable effects on structural encoding of emotional face expressions.
        Psychopharmacology (Berl). 2013; 225: 227-239
        • State M.W.
        • Sestan N.
        The emerging biology of autism spectrum disorders.
        Science. 2012; 337: 1301-1303
        • Lutchmaya S.
        • Baron-Cohen S.
        • Raggatt P.
        Foetal testosterone and eye contact in 12-month-old human infants.
        Infant Behav Dev. 2002; 25: 327-335
        • Christine Knickmeyer R.
        • Baron-Cohen S.
        Fetal testosterone and sex differences.
        Early Hum Dev. 2006; 82: 755-760
        • Gong P.
        • Madak-erdogan Z.
        • Li J.
        • Cheng J.
        • Greenlief C.M.
        • Helferich W.
        • et al.
        Transcriptomic analysis identifies gene networks regulated by estrogen receptor α ( ER α ) and ER β that control distinct effects of different botanical estrogens.
        Nucl Recept Signal. 2014; 12: 1-13
        • Mahrt E.J.
        • Perkel D.J.
        • Tong L.
        • Rubel E.W.
        • Portfors C.V.
        Engineered deafness reveals that mouse courtship vocalizations do not require auditory experience.
        J Neurosci. 2013; 33: 5573-5583