Autistic-like behaviors in mice with shank2 deficiency normalized by potentiation of NMDAR functionality

Abstract

Autism spectrum disorder (ASD) is a pervasive developmental disorder characterized by impaired social interaction and communication, and repetitive behaviors and restricted interests. ASD has a strong genetic component and etiologically heterogeneous with various genetic determinants. Shank2 is a multi-domain scaffolding protein and signaling adaptor enriched at excitatory neuronal synapses, and mutations in the human SHANK2 gene have recently been associated with ASD and intellectual disability. Although ASD associated genes are increasingly identified and studied using various approaches, further efforts are required to delineate important causal mechanisms with the potential for therapeutic application. Here I show that Shank2-mutant ($Shank2^{-/-}$) mice carrying a mutation identical to the ASD-associated microdeletion in the human SHANK2 gene exhibit ASD-like behaviors including impaired social interaction, abrogated social communication, and repetitive jumping. These mice show a marked decrease in N-methyl-D-aspartate glutamate receptor (NMDAR) function. Treatment of $Shank2^{-/-}$ mice with a positive allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), which enhances NMDAR function via mGluR5 activation, improves social interaction and normalizes NMDAR function. Moreover, direct stimulation of NMDARs with D-cycloserine, a partial agonist of NMDARs, yields similar results. These results suggest reduced NMDAR function may contribute to the development of ASD-like phenotypes in $Shank2^{-/-}$ mice, and mGluR modulation of NMDARs offers a potential strategy to treat ASD.