PSD-95 Is Essential for Hallucinogen and Atypical Antipsychotic Drug Actions at Serotonin Receptors
Journal of Neuroscience – June 03, 2009
Source: OpenAlex
Summary
PSD-95, known for regulating ionotropic glutamate signaling at the postsynaptic density, surprisingly modulates serotonergic 5-HT2A metabotropic receptor function, crucial for hallucinogen and antipsychotic actions. PSD-95 is essential for normal 5-HT receptor expression; without it, 5-HT2A-mediated responses are abnormal. This neuroscience and neuropharmacology research expands understanding of receptor mechanisms and signaling in cell biology and pharmacology, impacting postsynaptic potential, long-term depression, and related biology, chemistry, and metabotropic glutamate receptors.
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.