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

Abstract

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.

Decreased expression of mGluR5 within the dorsolateral prefrontal cortex in autism and increased microglial number in mGluR5 knockout mice: Pathophysiological and neurobehavioral implications

“…Our findings of a reduced gene expression of Shank3 and PLCB1 in the DLPFC are also in keeping with reduced mGluR5 signalling in ASD as the Shank family of proteins interact directly with mGluR5 through binding of Homer and PLC to positively regulate signalling. It is noteworthy however, that a recent study by Chung et al, demonstrated that social interaction deficits seen in an insulin receptor substrate protein, 53 kDA (IRSp53 À/À ) knockout mouse could be corrected by the NMDAR antagonist memantine or via the mGluR5 antagonist MPEP (Chung et al, 2015). This opposing finding to that described by Won et al, in their SHANK2 mutant mouse is of interest given the proximity of IRSp53 to the SHANK family of proteins.…”

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…A C C E P T E D M A N U S C R I P T spines and perforated PSDs (a measure of maturity) in the hippocampus 212 . Hippocampal neurons from IRSp53 −/− mice have been reported to exhibit stabilized F-actin and suppressed basal cofilin activity (i.e.…”

“…Hippocampal neurons from IRSp53 −/− mice have been reported to exhibit stabilized F-actin and suppressed basal cofilin activity (i.e. increased phosphorylation as a measure of inactivity) 212 . These animals also display enhanced NMDA receptor function, as well as social and cognitive deficits similar to those observed in psychiatric disorders 212 .…”

“…increased phosphorylation as a measure of inactivity) 212 . These animals also display enhanced NMDA receptor function, as well as social and cognitive deficits similar to those observed in psychiatric disorders 212 . Pharmacological suppression of NMDA receptor function can improve these behavioral deficits 212 , prompting the hypothesis that defective actin/membrane modulation in IRSp53-deficient dendritic spines could lead to social and cognitive deficits through NMDA receptor dysfunction.…”

Microglia in the pathogenesis of autism spectrum disorders

“…In contrast, the activation of inhibitory neurons in the medial prefrontal cortex did not affect social behaviors. Mice lacking IRSp53 (insulin receptor substrate protein, 53 kDa), which is an excitatory synaptic signaling scaffold protein and is also known as an ASD risk gene, displayed enhanced NMDA receptor function in the hippocampus and impaired social interaction and ultrasonic vocalization-mediated communication (Chung et al, 2015). The social deficits in the IRSp53−/− mice were rescued by an intraperitoneal injection of the NMDA antagonist memantine and by the metabotropic glutamate receptor 5 (mGluR5) antagonist MPEP.…”