Studies on Valproic acid-exposed mice and a conditional IRSp53-mutant mice

Abstract

Autism spectrum disorders (ASDs) represent psychiatric disorders characterized by social and communication deficits and repetitive behaviors. However, little is known about the underlying mechanisms. Valproic acid (VPA) is an agent known to cause ASD symptoms when an organism is prenatally exposed to VPA, but the underlying mechanism remains unclear. Previous studies have reported that NMDA receptor function is enhanced in prenatally VPA-treated animals. To study whether the enhanced NMDA receptor function accounts for the autistic-like behaviors observed in VPA mice, we treated these animals with memantine, an NMDAR antagonist. Acute memantine treatment rapidly rescued both the social deficits and repetitive behaviors observed in VPA mice, suggesting that enhanced NMDA receptor function may underlie VPA-induced autistic-like behaviors in mice. Loss of IRSp53, an actin-regulatory protein, in mice has been shown to cause NMDA receptor hyperfunction and autistic-like behaviors, including hyperactivity and social interaction and social communication deficits that are rescued by memantine treatment, further supporting the idea that NMDAR hyperfunction leads to autistic-like behaviors. For further understanding of cell type-specific contributions to the autistic-like behaviors in IRSp53 KO mice, we generated IRSp53 conditional KO (cKO) mice using IRSp53-flox mice and Dlx5/6-Cre mice that express Cre recombinases in GABAergic neurons abundant in brain regions including the striatum. IRSp53 Dlx5/6 cKO mice display hyperactivity and impaired recognition of social novelty but not social interaction deficits. Memantine treatment rescues social novelty recognition in these animals, but not hyperactivity. These results suggest that deletion of IRSp53 in Dlx5/6-positive neurons leads to hyperactivity and impaired social novel recognition, behavioral phenotypes that partially mimic those observed in IRSp53-null mice, and, together with results from VPA mice, suggest that enhanced NMDAR function contributes to autistic-like behaviors in mice.