Sociability and motor functions in Shank1 mutant mice

Autism is a neurodevelopmental disorder characterized by aberrant reciprocal social interactions, impaired communication, and repetitive behaviors. While the etiology remains unclear, strong evidence exists for a genetic component, and several synaptic genes have been implicated. SHANK genes encode a family of synaptic scaffolding proteins located postsynaptically on excitatory synapses. Mutations in SHANK genes have been detected in several autistic individuals. To understand the consequences of SHANK mutations relevant to the diagnostic and associated symptoms of autism, comprehensive behavioral phenotyping on a line of Shank1 mutant mice was conducted on multiple measures of social interactions, social olfaction, repetitive behaviors, anxiety-related behaviors, motor functions, and a series of control measures for physical abilities. Results from our comprehensive behavioral phenotyping battery indicated that adult Shank1 null mutant mice were similar to their wildtype and heterozygous littermates on standardized measures of general health, neurological reflexes and sensory skills. Motor functions were reduced in the null mutants on open field activity, rotarod, and wire hang, replicating and extending previous findings (Hung et al., 2008). A partial anxiety-like phenotype was detected in the null mutants in some components of the light ↔ dark task, as previously reported (Hung et al., 2008) but not in the elevated plus-maze. Juvenile reciprocal social interactions did not differ across genotypes. Interpretation of adult social approach was confounded by a lack of normal sociability in wildtype and heterozygous littermates. All genotypes were able to discriminate social odors on an olfactory habituation/dishabituation task. All genotypes displayed relatively high levels of repetitive self-grooming. Our findings support the interpretation that Shank1 null mice do not demonstrate autism-relevant social interaction deficits, but confirm and extend a role for Shank1 in motor functions.

[1]  G. Nygren,et al.  Sensory gating in young children with autism: Relation to age, IQ, and EEG gamma oscillations , 2008, Neuroscience Letters.

[2]  Guosong Liu,et al.  Regulation of Dendritic Spine Morphology and Synaptic Function by Shank and Homer , 2001, Neuron.

[3]  Jens Frahm,et al.  Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism , 2008, Proceedings of the National Academy of Sciences.

[4]  J. Crawley,et al.  Social transmission of food preference in mice: methodology and application to galanin-overexpressing transgenic mice. , 2003, Behavioral neuroscience.

[5]  Janet B W Williams.  Diagnostic and Statistical Manual of Mental Disorders , 2013 .

[6]  S. Schwartz,et al.  Terminal 22q deletion syndrome: a newly recognized cause of speech and language disability in the autism spectrum. , 2004, Pediatrics.

[7]  J. Crawley,et al.  Inbred strain differences in prepulse inhibition of the mouse startle response , 1997, Psychopharmacology.

[8]  T. Südhof,et al.  Increased anxiety‐like behavior in mice lacking the inhibitory synapse cell adhesion molecule neuroligin 2 , 2009, Genes, brain, and behavior.

[9]  D. Geschwind,et al.  Heterogeneous dysregulation of microRNAs across the autism spectrum , 2008, neurogenetics.

[10]  M. Sheng,et al.  The Shank family of scaffold proteins. , 2000, Journal of cell science.

[11]  M. Sheng,et al.  Degradation of Postsynaptic Scaffold GKAP and Regulation of Dendritic Spine Morphology by the TRIM3 Ubiquitin Ligase in Rat Hippocampal Neurons , 2010, PloS one.

[12]  D. Murphy,et al.  Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression , 2003, Biological Psychiatry.

[13]  F. Happé,et al.  Investigating the association between autistic-like and internalizing traits in a community-based twin sample. , 2009, Journal of the American Academy of Child and Adolescent Psychiatry.

[14]  H. McFarlane,et al.  Autism‐like behavioral phenotypes in BTBR T+tf/J mice , 2008, Genes, brain, and behavior.

[15]  Laurent Mottron,et al.  Novel de novo SHANK3 mutation in autistic patients , 2009, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[16]  J. Crawley,et al.  Social deficits, stereotypy and early emergence of repetitive behavior in the C58/J inbred mouse strain , 2010, Behavioural Brain Research.

[17]  R. Kahn,et al.  The 22q11.2 deletion in children: high rate of autistic disorders and early onset of psychotic symptoms. , 2006, Journal of the American Academy of Child and Adolescent Psychiatry.

[18]  L. Mucke,et al.  Abnormal social behaviors in mice lacking Fgf17 , 2008, Genes, brain, and behavior.

[19]  Edward S. Brodkin,et al.  BALB/c mice: Low sociability and other phenotypes that may be relevant to autism , 2007, Behavioural Brain Research.

[20]  D. Murphy,et al.  Abnormal anxiety‐related behavior in serotonin transporter null mutant mice: the influence of genetic background , 2003, Genes, brain, and behavior.

[21]  P. Seeburg,et al.  Complex, multimodal behavioral profile of the Homer1 knockout mouse , 2007, Genes, brain, and behavior.

[22]  Jacqueline Blundell,et al.  A Neuroligin-3 Mutation Implicated in Autism Increases Inhibitory Synaptic Transmission in Mice , 2007, Science.

[23]  Catherine Lord,et al.  Developmental trajectories of restricted and repetitive behaviors and interests in children with autism spectrum disorders , 2010, Development and Psychopathology.

[24]  S. Rogers,et al.  Annotation: what do we know about sensory dysfunction in autism? A critical review of the empirical evidence. , 2005, Journal of child psychology and psychiatry, and allied disciplines.

[25]  J. Crawley,et al.  Hyperalgesia and increased neuropathic pain-like response in mice lacking galanin receptor 1 receptors , 2003, Neuroscience.

[26]  M. Bouvard,et al.  Case with autistic syndrome and chromosome 22q13.3 deletion detected by FISH. , 2000, American journal of medical genetics.

[27]  T. Südhof,et al.  Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments , 2009, Proceedings of the National Academy of Sciences.

[28]  E. Alleva,et al.  Ontogeny of amicable social behavior in the mouse: gender differences and ongoing isolation outcomes. , 1993, Developmental psychobiology.

[29]  Valerie J. Bolivar,et al.  Assessing autism-like behavior in mice: Variations in social interactions among inbred strains , 2007, Behavioural Brain Research.

[30]  S S Moy,et al.  Social approach in genetically engineered mouse lines relevant to autism , 2009, Genes, brain, and behavior.

[31]  Timothy M. DeLorey,et al.  Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: A potential model of autism spectrum disorder , 2008, Behavioural Brain Research.

[32]  I. Branchi.  The mouse communal nest: Investigating the epigenetic influences of the early social environment on brain and behavior development , 2009, Neuroscience & Biobehavioral Reviews.

[33]  G. Laviola,et al.  The developmental psychobiology of behavioural plasticity in mice: the role of social experiences in the family unit , 1998, Neuroscience & Biobehavioral Reviews.

[34]  Y. Hata,et al.  Synamon, a Novel Neuronal Protein Interacting with Synapse-associated Protein 90/Postsynaptic Density-95-associated Protein* , 1999, The Journal of Biological Chemistry.

[35]  G. Laviola,et al.  Scoring of Social Interactions and Play in Mice During Adolescence , 2005, Current protocols in toxicology.

[36]  L. Jocelyn,et al.  Genetic evaluation of pervasive developmental disorders: the terminal 22q13 deletion syndrome may represent a recognizable phenotype , 2000, Clinical genetics.

[37]  Jacqueline N. Crawley,et al.  A Proposed Test Battery and Constellations of Specific Behavioral Paradigms to Investigate the Behavioral Phenotypes of Transgenic and Knockout Mice , 1997, Hormones and Behavior.

[38]  M. C. Phelan.  Deletion 22q13.3 syndrome , 2008, Orphanet journal of rare diseases.

[39]  T. Südhof,et al.  Neuroligin-1 Deletion Results in Impaired Spatial Memory and Increased Repetitive Behavior , 2010, The Journal of Neuroscience.

[40]  Garet P Lahvis,et al.  Social reward among juvenile mice , 2007, Genes, brain, and behavior.

[41]  F. Goodwin,et al.  Preliminary report of a simple animal behavior model for the anxiolytic effects of benzodiazepines , 1980, Pharmacology Biochemistry and Behavior.

[42]  Kiyoshi Inoue,et al.  Abnormal Behavior in a Chromosome- Engineered Mouse Model for Human 15q11-13 Duplication Seen in Autism , 2009, Cell.

[43]  R. Paylor,et al.  The use of behavioral test batteries, II: Effect of test interval , 2006, Physiology & Behavior.

[44]  R. Nonneman,et al.  Social approach and repetitive behavior in eleven inbred mouse strains , 2008, Behavioural Brain Research.

[45]  Christian R Marshall,et al.  Contribution of SHANK3 mutations to autism spectrum disorder. , 2007, American journal of human genetics.

[46]  Ute Moog,et al.  Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation , 2010, Nature Genetics.

[47]  G. Baird,et al.  Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. , 2008, Journal of the American Academy of Child and Adolescent Psychiatry.

[48]  R. Jope,et al.  GSK3 Influences Social Preference and Anxiety-Related Behaviors during Social Interaction in a Mouse Model of Fragile X Syndrome and Autism , 2010, PloS one.

[49]  J. Crawley.  Mouse Behavioral Assays Relevant to the Symptoms of Autism * , 2007, Brain pathology.

[50]  Jacqueline N. Crawley,et al.  Social deficits in BTBR T + tf/J mice are unchanged by cross-fostering with C57BL/6J mothers , 2007, International Journal of Developmental Neuroscience.

[51]  J. Hohmann,et al.  Galanin receptor subtype 2 (GalR2) null mutant mice display an anxiogenic-like phenotype specific to the elevated plus-maze , 2007, Pharmacology Biochemistry and Behavior.

[52]  D. Sibley,et al.  Behavioral characterization of dopamine D5 receptor null mutant mice. , 2001, Behavioral neuroscience.

[53]  P. Worley,et al.  Shank Expression Is Sufficient to Induce Functional Dendritic Spine Synapses in Aspiny Neurons , 2005, The Journal of Neuroscience.

[54]  Hewlet G McFarlane,et al.  Social Approach Behaviors are Similar on Conventional Versus Reverse Lighting Cycles, and in Replications Across Cohorts, in BTBR T+ tf/J, C57BL/6J, and Vasopressin Receptor 1B Mutant Mice , 2007, Frontiers in behavioral neuroscience.

[55]  S. Paul,et al.  Genetic analysis of anxiety-related behaviors and responses to benzodiazepine-related drugs in AXB and BXA recombinant inbred mouse strains , 1995, Behavior genetics.

[56]  Thomas Bourgeron,et al.  A synaptic trek to autism , 2009, Current Opinion in Neurobiology.

[57]  Mark F Bear,et al.  Smaller Dendritic Spines, Weaker Synaptic Transmission, but Enhanced Spatial Learning in Mice Lacking Shank1 , 2008, The Journal of Neuroscience.

[58]  F. Champagne,et al.  Maternal Care, Gene Expression, and the Development of Individual Differences in Stress Reactivity , 1999, Annals of the New York Academy of Sciences.

[59]  S. Hepburn,et al.  Parent Reports of Sensory Symptoms in Toddlers with Autism and Those with Other Developmental Disorders , 2003, Journal of autism and developmental disorders.

[60]  A. Minassian,et al.  Sensorimotor Gating Deficits in Adults with Autism , 2007, Biological Psychiatry.

[61]  E. Keverne,et al.  Natural variations in postpartum maternal care in inbred and outbred mice , 2007, Physiology & Behavior.

[62]  Joseph D. Buxbaum,et al.  Multiple rare variants in the etiology of autism spectrum disorders , 2009, Dialogues in clinical neuroscience.

[63]  Dai Zhang,et al.  Association study of SHANK3 gene polymorphisms with autism in Chinese Han population , 2009, BMC Medical Genetics.

[64]  D Kim,et al.  Variations in the behaviors to novel objects among five inbred strains of mice , 2005, Genes, brain, and behavior.

[65]  T. Hökfelt,et al.  Galanin and spinal nociceptive mechanisms: Recent results from transgenic and knock-out models , 2005, Neuropeptides.

[66]  S. File,et al.  A review of 25 years of the social interaction test. , 2003, European journal of pharmacology.

[67]  Garet P. Lahvis,et al.  Affiliative Behavior, Ultrasonic Communication and Social Reward Are Influenced by Genetic Variation in Adolescent Mice , 2007, PloS one.

[68]  R. Nonneman,et al.  Impaired sociability and cognitive function in Nrcam-null mice , 2009, Behavioural Brain Research.

[69]  E. Alleva,et al.  Communal nesting, an early social enrichment, affects social competences but not learning and memory abilities at adulthood , 2007, Behavioural Brain Research.

[70]  Inês Sousa,et al.  Copy number variation and association analysis of SHANK3 as a candidate gene for autism in the IMGSAC collection , 2009, European Journal of Human Genetics.

[71]  A description of the ontogeny of mouse agonistic behavior. , 1998 .

[72]  J. Frahm,et al.  Neuroligin‐3‐deficient mice: model of a monogenic heritable form of autism with an olfactory deficit , 2009, Genes, brain, and behavior.

[73]  J. Shine,et al.  Galanin GAL-R1 Receptor Null Mutant Mice Display Increased Anxiety-Like Behavior Specific to the Elevated Plus-Maze , 2003, Neuropsychopharmacology.

[74]  D. Richter,et al.  Fragile X Mental Retardation Protein Regulates the Levels of Scaffold Proteins and Glutamate Receptors in Postsynaptic Densities* , 2009, The Journal of Biological Chemistry.

[75]  J. Crawley,et al.  Simple Behavioral Assessment of Mouse Olfaction , 2009, Current protocols in neuroscience.

[76]  J. Crawley,et al.  Postnatal lesion evidence against a primary role for the corpus callosum in mouse sociability , 2009, The European journal of neuroscience.

[77]  Shiaoching Gong,et al.  Minimal aberrant behavioral phenotypes of neuroligin‐3 R451C knockin mice , 2008, Autism research : official journal of the International Society for Autism Research.

[78]  Klaus-Peter Lesch,et al.  Mice Lacking the Serotonin Transporter Exhibit 5-HT1A Receptor-Mediated Abnormalities in Tests for Anxiety-like Behavior , 2003, Neuropsychopharmacology.

[79]  Thomas Bourgeron,et al.  Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders , 2007, Nature Genetics.

[80]  Jacqueline N. Crawley,et al.  Social approach behaviors in oxytocin knockout mice: Comparison of two independent lines tested in different laboratory environments , 2007, Neuropeptides.

[81]  C. Lord,et al.  Restricted and Repetitive Behaviors in Young Children with Autism Spectrum Disorders , 2007, Journal of autism and developmental disorders.

[82]  Jill L Silverman,et al.  Repetitive Self-Grooming Behavior in the BTBR Mouse Model of Autism is Blocked by the mGluR5 Antagonist MPEP , 2010, Neuropsychopharmacology.

[83]  C. Hartman,et al.  Multiple Complex Developmental Disorder Delineated from PDD-NOS , 2007, Journal of autism and developmental disorders.

[84]  A. Fleming,et al.  Parental Behaviors in Rats and Mice , 2001, Current protocols in neuroscience.

[85]  C. Deng,et al.  Motor deficits in fibroblast growth factor receptor‐3 null mutant mice , 2001, Behavioural pharmacology.

[86]  M. Strawderman,et al.  Evidence for social anxiety and impaired social cognition in a mouse model of fragile X syndrome. , 2008, Behavioral neuroscience.

[87]  H. Cameron,et al.  The neuropeptide Y Y1 receptor subtype is necessary for the anxiolytic-like effects of neuropeptide Y, but not the antidepressant-like effects of fluoxetine, in mice , 2007, Psychopharmacology.

[88]  P. Worley,et al.  Shank, a Novel Family of Postsynaptic Density Proteins that Binds to the NMDA Receptor/PSD-95/GKAP Complex and Cortactin , 1999, Neuron.

[89]  Madhukar H. Trivedi,et al.  The pattern of sensory processing abnormalities in autism , 2006, Autism : the international journal of research and practice.

[90]  J. Crawley,et al.  Deficits in social behavior and reversal learning are more prevalent in male offspring of VIP deficient female mice , 2008, Experimental Neurology.

[91]  J. Crawley,et al.  Evaluation of an anxiety-related phenotype in galanin overexpressing transgenic mice , 2002, Journal of Molecular Neuroscience.

[92]  M. Geyer,et al.  Effects of strain and serotonergic agents on prepulse inhibition and habituation in mice , 2000, Neuropharmacology.

[93]  J. Crawley,et al.  Further characterization of a simple, automated exploratory model for the anxiolytic effects of benzodiazepines , 1983, Pharmacology Biochemistry and Behavior.

[94]  Gary D Bader,et al.  Functional impact of global rare copy number variation in autism spectrum disorders , 2010, Nature.

[95]  R. Mason,et al.  Pten haploinsufficiency accelerates formation of high-grade astrocytomas. , 2008, Cancer research.

[96]  Edward S. Brodkin,et al.  A Mouse Model System for Genetic Analysis of Sociability: C57BL/6J Versus BALB/cJ Inbred Mouse Strains , 2006, Biological Psychiatry.

[97]  Eunjoon Kim,et al.  Characterization of the Shank Family of Synaptic Proteins , 1999, The Journal of Biological Chemistry.

[98]  J. Powell,et al.  Molecular and phenotypic characterization of ring chromosome 22 , 2005, American journal of medical genetics. Part A.

[99]  Angelica Ronald,et al.  The ‘Fractionable Autism Triad’: A Review of Evidence from Behavioural, Genetic, Cognitive and Neural Research , 2008, Neuropsychology Review.

[100]  Jacqueline N. Crawley,et al.  Mouse behavioral tasks relevant to autism: Phenotypes of 10 inbred strains , 2007, Behavioural Brain Research.

[101]  J. Bockmann,et al.  Differential expression and dendritic transcript localization of Shank family members: identification of a dendritic targeting element in the 3′ untranslated region of Shank1 mRNA , 2004, Molecular and Cellular Neuroscience.

[102]  Tony Charman,et al.  Auditory discrimination and auditory sensory behaviours in autism spectrum disorders , 2009, Neuropsychologia.

[103]  C. Hoogenraad,et al.  Relative and Absolute Quantification of Postsynaptic Density Proteome Isolated from Rat Forebrain and Cerebellum*S , 2006, Molecular & Cellular Proteomics.

[104]  T. Boeckers,et al.  Proline-Rich Synapse-Associated Protein-1/Cortactin Binding Protein 1 (ProSAP1/CortBP1) Is a PDZ-Domain Protein Highly Enriched in the Postsynaptic Density , 1999, The Journal of Neuroscience.

[105]  C. Lord,et al.  Behavioural phenotyping assays for mouse models of autism , 2010, Nature Reviews Neuroscience.