title: Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism.
abstract: Shank3 is a multi-domain, synaptic scaffolding protein that organizes proteins in the postsynaptic density of excitatory synapses. Clinical studies suggest that ∼ 0.5% of autism spectrum disorder (ASD) cases may involve SHANK3 mutation/deletion. Patients with SHANK3 mutations exhibit deficits in cognition along with delayed/impaired speech/language and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how mutation/deletion of SHANK3 might alter brain function leading to ASD, we have independently created mice with deletion of Shank3 exons 4-9, a region implicated in ASD patients. We find that homozygous deletion of exons 4-9 (Shank3(e4-9) KO) results in loss of the two highest molecular weight isoforms of Shank3 and a significant reduction in other isoforms. Behaviorally, both Shank3(e4-9) heterozygous (HET) and Shank3(e4-9) KO mice display increased repetitive grooming, deficits in novel and spatial object recognition learning and memory, and abnormal ultrasonic vocalizations. Shank3(e4-9) KO mice also display abnormal social interaction when paired with one another. Analysis of synaptosome fractions from striata of Shank3(e4-9) KO mice reveals decreased Homer1b/c, GluA2, and GluA3 expression. Both Shank3(e4-9) HET and KO demonstrated a significant reduction in NMDA/AMPA ratio at excitatory synapses onto striatal medium spiny neurons. Furthermore, Shank3(e4-9) KO mice displayed reduced hippocampal LTP despite normal baseline synaptic transmission. Collectively these behavioral, biochemical and physiological changes suggest Shank3 isoforms have region-specific roles in regulation of AMPAR subunit localization and NMDAR function in the Shank3(e4-9) mutant mouse model of autism.
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Jaramillo
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Haley E
authors.initials: HE
authors.lastname: Speed
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Xuan
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Reimers
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Shunan
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas.|Department of Psychiatry and Neuroscience Graduate Program, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Powell
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics*; D001522:Behavior, Animal / Q000502:physiology*; D003342:Corpus Striatum / Q000503:physiopathology*; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics*; D005260:Female; D008297:Male; D051379:Mice; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics*; D017384:Sequence Deletion; D013569:Synapses / Q000502:physiology; 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