PSD-95 is essential for hallucinogen and atypical antipsychotic drug actions at serotonin receptors

Here, we report that postsynaptic density protein of 95 kDa (PSD-95), a postsynaptic density scaffolding protein, classically conceptualized as being essential for the regulation of ionotropic glutamatergic signaling at the postsynaptic membrane, plays an unanticipated and essential role in mediating the actions of hallucinogens and atypical antipsychotic drugs at 5-HT _2A and 5-HT_2C serotonergic G-protein-coupled receptors. We show that PSD-95 is crucial for normal 5-HT_2A and 5-HT_2C expression in vivo and that PSD-95 maintains normal receptor expression by promoting apical dendritic targeting and stabilizing receptor turnover in vivo. Significantly, 5-HT_2A-and 5-HT_2Cmediated downstream signaling is impaired in PSD-95^null mice, and the 5-HT _2A-mediated head-twitch response is abnormal. Furthermore, the ability of 5-HT_2A inverse agonists to normalize behavioral changes induced by glutamate receptor antagonists is abolished in the absence of PSD-95 in vivo. These results demonstrate that PSD-95, in addition to the well known role it plays in scaffolding macromolecular glutamatergic signaling complexes, profoundly modulates metabotropic 5-HT_2A and 5-HT_2C receptor function.