PSD-95 Is Essential for Hallucinogen and Atypical Antipsychotic Drug Actions at Serotonin Receptors

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Abstract
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-HT2Aand 5-HT2Cserotonergic G-protein-coupled receptors. We show that PSD-95 is crucial for normal 5-HT2Aand 5-HT2Cexpressionin vivoand that PSD-95 maintains normal receptor expression by promoting apical dendritic targeting and stabilizing receptor turnoverin vivo. Significantly, 5-HT2A- and 5-HT2C-mediated downstream signaling is impaired inPSD-95nullmice, and the 5-HT2A-mediated head-twitch response is abnormal. Furthermore, the ability of 5-HT2Ainverse agonists to normalize behavioral changes induced by glutamate receptor antagonists is abolished in the absence of PSD-95in 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-HT2Aand 5-HT2Creceptor function.

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