Autistic behavior and Region-specific impairments of synaptic transmission in mice lacking IRSp53

Abstract

Autism Spectrum Disorders (ASD) is surprisingly common and numerous synaptic molecules have been implicated in ASD. IRSp53 (insulin receptor tyrosine kinase substrate of 53 kDa) is an abundant postsynaptic protein and has also been reported to be associated with ASD. IRSp53 plays a key role in the regulation of actin dynamics by acting downstream of Cdc42 and Rac. A previous in vitro study with primary hippocampal neurons shows that IRSp53 regulates spine density and morphology while subsequent in vivo studies using IRSp53 knockout (KO) mice demonstrated that the mice do not similar morphological changes but display other phenotypes such as enhanced NMDA receptor (NMDAR) transmission, enhanced LTP and impaired learning and memory. We have tested whether IRSp53 KO mice displat ASD-like behaviors, based on the recent evidence of the association between ASD and IRSp53. IRSp53 KO mice demonstrate two core symptoms of ASD; impaired sociability and deficits in communication. IRSp53 KO mice show enhanced NMDA receptor-dependent synaptic transmission, suggesting that this may be a key mechanism underlying the development of ASD. Our present study suggests that impaired actin remodeling underlies the increased NMDAR transmission in the hippocampus. We also evaluated the medial prefrontal cortex (mPFC), a brain structure known to be associated with ASD. Intriguingly, the mPFC show normal NMDAR-mediated transmission, but displays reduced spine density and reduced excitatory synaptic transmission. Thus, genetic deletion of IRSp53 leads to brain region-specific impairments in structure, spine morphology, synaptic transmission, which may lead to ASD-like behaviors. Importantly two different drugs that inhibit glutamate receptors, namely MPEP (2-methyl-6-phenylethynyl-pyridine) and memantine, were effective normalizing social interaction in IRSp53 KO mice. Our results show that the enhanced NMDAR function may underlie the development of ASD-like behaviors in IRSp53 KO mice a...