Shank3 mutant mice display autistic-like behaviours and striatal dysfunction

Abstract

Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. Shank3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for development of 22q13 deletion syndrome (Phelan-McDermid Syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for Shank3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic like-behaviours in mice.

Substantia nigra dopaminergic neurons and striatal interneurons are engaged in three parallel but interdependent postnatal neurotrophic circuits

“…For the preparation of brain slices, we used the N‐methyl‐ d ‐glucamine (NMDG) protective recovery method described by the laboratory of Guoping Feng (Peça et al, 2011; Ting, Daigle, Chen, & Feng, 2014; Zhao et al, 2011). In brief, 4‐ and 10‐month‐old mice of both sexes were anesthetized with 2% tribromoethanol (0.15 ml/10 mg) and rapidly decapitated.…”

Shank mutant mice as an animal model of autism

“…In fact, another study includes a similar deletion, which excised exon 4 to 7 (Shank3 e4 -7 ), although the majority of the results from that study refer to a downstream deletion of exons 13-16, resulting in the knockout of many shorter isoforms not affected in the other studies [72]. In addition, two recent studies have used gene expression in cultured hippocampal neurons to look at the subcellular mechanisms of Shank3, and the effect of point mutations in the ankyrin repeats domain associated with autism ( [14,73]; tables 3 and 4).…”

“…Peça et al make use of a Shank3 deletion of exons 13-16 in the PDZ region, resulting in the absence of all but the shortest two identified forms of Shank3 [72] consisting only of the proline-rich region and/or the SAM domain. The mice in this study display a comprehensive and strong autism-typical phenotype: impaired social interactions in a three-chamber task, as well as a lack of social novelty preference; repetitive behaviour, in the form of self-grooming to the extent of self-inflicted lesions; anxiety-related behaviour, as measured by an elevated zero maze, a light-dark test, and a lack of rearing in the open field.…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…Shank3-null mice exhibit deficits in synaptic functioning such as impaired AMPAR trafficking, glutamatergic transmission, and long-term potentiation [158,159]. These mice recapitulate aberrant symptoms in social behavior, communication, repetitive behaviors, motor functioning, and learning/memory [158][159][160]. However, SHANK3 is not the only gene responsible for this 22q13 deletion syndrome [161].…”