title: Novel Shank3 mutant exhibits behaviors with face validity for autism and altered striatal and hippocampal function.
abstract: Mutations/deletions in the SHANK3 gene are associated with autism spectrum disorders and intellectual disability. Here, we present electrophysiological and behavioral consequences in novel heterozygous and homozygous mice with a transcriptional stop cassette inserted upstream of the PDZ domain-coding exons in Shank3 (Shank3E13). Insertion of a transcriptional stop cassette prior to exon 13 leads to loss of the two higher molecular weight isoforms of Shank3. Behaviorally, both Shank3E13heterozygous (HET) and homozygous knockout (KO) mice display increased repetitive grooming, deficits in social interaction tasks, and decreased rearing. Shank3E13KO mice also display deficits in spatial memory in the Morris water maze task. Baseline hippocampal synaptic transmission and short-term plasticity are preserved in Shank3E13HET and KO mice, while both HET and KO mice exhibit impaired hippocampal long-term plasticity. Additionally, Shank3E13HET and KO mice display impaired striatal glutamatergic synaptic transmission. These results demonstrate for the first time in this novel Shank3 mutant that both homozygous and heterozygous mutation of Shank3 lead to behavioral abnormalities with face validity for autism along with widespread synaptic dysfunction. Autism Res 2017, 10: 42-65. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.
authors: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors: Thomas C
authors: TC
authors: Jaramillo
authors: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors: Haley E
authors: HE
authors: Speed
authors: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors: Zhong
authors: Z
authors: Xuan
authors: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors: Jeremy M
authors: JM
authors: Reimers
authors: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors: Christine Ochoa
authors: CO
authors: Escamilla
authors: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors: Travis P
authors: TP
authors: Weaver
authors: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors: Shunan
authors: S
authors: Liu
authors: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors: Irina
authors: I
authors: Filonova
authors: Department of Psychiatry and Neuroscience Graduate Program, University of Texas Southwestern Medical Center, Dallas, Texas.
authors: Craig M
authors: CM
authors: Powell
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000503:physiopathology*; D001522:Behavior, Animal; D015153:Blotting, Western; D003342:Corpus Striatum / Q000503:physiopathology*; D004195:Disease Models, Animal; D005091:Exons; D005260:Female; D006624:Hippocampus / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D015203:Reproducibility of Results; D017384:Sequence Deletion; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; C492356:Shank3 protein, mouse
keywords: Phelan-McDermid syndrome; Shank3; autism spectrum disorder; grooming; mouse model; social interaction