title: Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism.
abstract: Human neuroimaging studies suggest that aberrant neural connectivity underlies behavioural deficits in autism spectrum disorders (ASDs), but the molecular and neural circuit mechanisms underlying ASDs remain elusive. Here, we describe a complete knockout mouse model of the autism-associated Shank3 gene, with a deletion of exons 4-22 (Δe4-22). Both mGluR5-Homer scaffolds and mGluR5-mediated signalling are selectively altered in striatal neurons. These changes are associated with perturbed function at striatal synapses, abnormal brain morphology, aberrant structural connectivity and ASD-like behaviour. In vivo recording reveals that the cortico-striatal-thalamic circuit is tonically hyperactive in mutants, but becomes hypoactive during social behaviour. Manipulation of mGluR5 activity attenuates excessive grooming and instrumental learning differentially, and rescues impaired striatal synaptic plasticity in Δe4-22(-/-) mice. These findings show that deficiency of Shank3 can impair mGluR5-Homer scaffolding, resulting in cortico-striatal circuit abnormalities that underlie deficits in learning and ASD-like behaviours. These data suggest causal links between genetic, molecular, and circuit mechanisms underlying the pathophysiology of ASDs.
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Bey
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Brittany M
authors.initials: BM
authors.lastname: Katz
authors.affiliation: Department of Radiology, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Badea
authors.affiliation: Department of Psychology and Neuroscience, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Namsoo
authors.initials: N
authors.lastname: Kim
authors.affiliation: Department of Psychology and Neuroscience, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: David
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina 27710, USA.|Department of Neurobiology, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Lara J
authors.initials: LJ
authors.lastname: Duffney
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Psychology and Neuroscience, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Mague
authors.affiliation: Department of Neurobiology, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Samuel W
authors.initials: SW
authors.lastname: Hulbert
authors.affiliation: Department of Cell Biology, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Nisha
authors.initials: N
authors.lastname: Dutta
authors.affiliation: Department of Psychology and Neuroscience, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Volodya
authors.initials: V
authors.lastname: Hayrapetyan
authors.affiliation: Department of Psychology and Neuroscience, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Chunxiu
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Psychology and Neuroscience, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Gaidis
authors.affiliation: Department of Neurobiology, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Shengli
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Ophthalmology, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Jin-Dong
authors.initials: JD
authors.lastname: Ding
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina 27710, USA.|Department of Child Health Care, The Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Leeyup
authors.initials: L
authors.lastname: Chung
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Ramona M
authors.initials: RM
authors.lastname: Rodriguiz
authors.affiliation: Department of Neurobiology, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, North Carolina 27599, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Weinberg
authors.affiliation: Department of Neurobiology, Duke University, Durham, North Carolina 27710, USA.|Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina 27710, USA.|Department of Cell Biology, Duke University, Durham, North Carolina 27710, USA.|Duke Institute for Brain Sciences, Duke University, Durham, North Carolina 27710, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina 27710, USA.|Duke Institute for Brain Sciences, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Kafui
authors.initials: K
authors.lastname: Dzirasa
authors.affiliation: Department of Psychology and Neuroscience, Duke University, Durham, North Carolina 27710, USA.|Duke Institute for Brain Sciences, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Yin
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina 27710, USA.|Department of Neurobiology, Duke University, Durham, North Carolina 27710, USA.|Duke Institute for Brain Sciences, Duke University, Durham, North Carolina 27710, USA.|University Program in Genetics and Genomics, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology*; D003342:Corpus Striatum / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D000072233:Homer Scaffolding Proteins / Q000378:metabolism*; D006801:Humans; D036881:Long-Term Synaptic Depression; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins; D008959:Models, Neurological; D009415:Nerve Net / Q000473:pathology / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D017384:Sequence Deletion; D012919:Social Behavior
chemical_list: C578936:Grm5 protein, mouse; D000072233:Homer Scaffolding Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D064529:Receptor, Metabotropic Glutamate 5; C492357:SHANK3 protein, human; C492356:Shank3 protein, mouse