Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression

Enhanced NMDA receptor function and social interaction deficits are observed in mice lacking the excitatory postsynaptic scaffolding protein IRSp53. Reducing NMDAR activity by pharmacological methods rescues the impaired social interaction observed in these mice. This suggests that enhanced NMDA receptor function may be associated with social deficits. Social deficits are observed in diverse psychiatric disorders, including autism spectrum disorders and schizophrenia. We found that mice lacking the excitatory synaptic signaling scaffold IRSp53 (also known as BAIAP2) showed impaired social interaction and communication. Treatment of IRSp53 −/− mice, which display enhanced NMDA receptor (NMDAR) function in the hippocampus, with memantine, an NMDAR antagonist, or MPEP, a metabotropic glutamate receptor 5 antagonist that indirectly inhibits NMDAR function, normalized social interaction. This social rescue was accompanied by normalization of NMDAR function and plasticity in the hippocampus and neuronal firing in the medial prefrontal cortex. These results, together with the reduced NMDAR function implicated in social impairments, suggest that deviation of NMDAR function in either direction leads to social deficits and that correcting the deviation has beneficial effects.