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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Abbas, AI; Yadav, PN; Yao, W-D; Arbuckle, MI; Grant, SGN; Caron, MG; Roth, BL

Published Date

  • June 3, 2009

Published In

Volume / Issue

  • 29 / 22

Start / End Page

  • 7124 - 7136

PubMed ID

  • 19494135

Pubmed Central ID

  • 19494135

Electronic International Standard Serial Number (EISSN)

  • 1529-2401

Digital Object Identifier (DOI)

  • 10.1523/JNEUROSCI.1090-09.2009

Language

  • eng

Conference Location

  • United States