AMPA receptor-control essential for modulation of social behaviors

抄録

Social interaction deficit is one of the hallmarks of autism spectrum disorders (ASD). Despite the spotlight in ASD diagnosis, social impairment still longs for a cure. The main reasons for the slow progress are the complexity of social behavior function and the heterogeneity of ASD etiology and pathophysiology. The excitatory-inhibitory imbalance has been strongly suggested to influence the development of ASD and a dysregulated glutamatergic neurotransmission is a major facet of this imbalance. Various reports implicate the involvement of NMDA receptor transmission in the abnormalities of ASD but few have tried to uncover the role of AMPA receptors. As early responders to glutamate release in the synapse, AMPA receptors are likely playing a role in ASD pathophysiology. In this report, we investigated the role of AMPA modulation in two aspects of ASD models, the increased and decreased excitatory neurotransmission signals found in the VPA-exposed offspring and CNTNAP2 KO mice, respectively. To affirm these models, we showed that the VPA mice have increased NR2B and GluR1 expressions in the prefrontal cortex along with increased amplitude of miniature excitatory postsynaptic currents (mEPSCs) while the CNTNAP2 mice have decreased NR2A, NR2B and GluR1 expressions with reduced mEPSCs. To address their abnormalities, we treated each model with AMPA receptor antagonist (CP465022) and agonist (PF4778574) for VPA mice and CNTNAP2 KO mice, respectively. Interestingly, the social behavior deficits were normalized in both models but repetitive and hyperactive behaviors were not changed. We then hypothesized that a balanced AMPA receptor modulation is important for social behavior function. We tested this hypothesis by injecting AMPA agonist or antagonist in wildtype ICR mice. Remarkably, either of these modulators affected the social behaviors in mice without inducing repetitive or hyperactive behaviors, validating our hypothesis. This study offers a novel understanding of the connection of AMPA receptors to the pathophysiology of ASD and demonstrates that AMPA receptor modulation is a candidate target for the treatment of social behavioral deficits in ASD.