title: Autism-Associated Insertion Mutation (InsG) of Shank3 Exon 21 Causes Impaired Synaptic Transmission and Behavioral Deficits.
abstract: SHANK3 (also known as PROSAP2) is a postsynaptic scaffolding protein at excitatory synapses in which mutations and deletions have been implicated in patients with idiopathic autism, Phelan-McDermid (aka 22q13 microdeletion) syndrome, and other neuropsychiatric disorders. In this study, we have created a novel mouse model of human autism caused by the insertion of a single guanine nucleotide into exon 21 (Shank3(G)). The resulting frameshift causes a premature STOP codon and loss of major higher molecular weight Shank3 isoforms at the synapse. Shank3(G/G) mice exhibit deficits in hippocampus-dependent spatial learning, impaired motor coordination, altered response to novelty, and sensory processing deficits. At the cellular level, Shank3(G/G) mice also exhibit impaired hippocampal excitatory transmission and plasticity as well as changes in baseline NMDA receptor-mediated synaptic responses. This work identifies clear alterations in synaptic function and behavior in a novel, genetically accurate mouse model of autism mimicking an autism-associated insertion mutation. Furthermore, these findings lay the foundation for future studies aimed to validate and study region-selective and temporally selective genetic reversal studies in the Shank3(G/G) mouse that was engineered with such future experiments in mind.
authors.affiliation: Departments of Neurology and Neurotherapeutics and.
authors.forename: Haley E
authors.initials: HE
authors.lastname: Speed
authors.affiliation: Departments of Neurology and Neurotherapeutics and.
authors.forename: Mehreen
authors.initials: M
authors.lastname: Kouser
authors.affiliation: Departments of Neurology and Neurotherapeutics and.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Xuan
authors.affiliation: Departments of Neurology and Neurotherapeutics and.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Reimers
authors.affiliation: Departments of Neurology and Neurotherapeutics and.
authors.forename: Christine F
authors.initials: CF
authors.lastname: Ochoa
authors.affiliation: Departments of Neurology and Neurotherapeutics and.
authors.forename: Natasha
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Departments of Neurology and Neurotherapeutics and.
authors.forename: Shunan
authors.initials: S
authors.lastname: Liu
authors.affiliation: Departments of Neurology and Neurotherapeutics and Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8813 craig.powell@utsouthwestern.edu.
authors.forename: Craig M
authors.identifier: http://orcid.org/0000-0001-5451-2165
authors.initials: CM
authors.lastname: Powell
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D005091:Exons / Q000235:genetics*; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D006120:Grooming / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D008124:Locomotion / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000502:physiology; D001523:Mental Disorders / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D016254:Mutagenesis, Insertional / Q000379:methods*; D009154:Mutation / Q000235:genetics*; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009425:Nesting Behavior / Q000502:physiology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D009435:Synaptic Transmission / Q000235:genetics*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; C492356:Shank3 protein, mouse; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D016202:N-Methylaspartate
keywords: Phelan–McDermid syndrome; Shank3; autism; behavior; postsynaptic density; synaptic plasticity