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

The scaffolding protein PSD-95, known for organizing glutamate receptors at synapses, also critically regulates serotonin 5-HT2A and 5-HT2C receptors. In mice lacking PSD-95, these serotonin receptors show reduced expression, abnormal distribution in dendrites, and impaired signaling. Hallucinogen-induced behaviors and the effects of atypical antipsychotics that target these receptors are disrupted. PSD-95 is essential for normal serotonergic receptor function, expanding its role beyond glutamate signaling.

Study at a glance

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-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 2C -mediated 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.