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The Journal of Neuroscience, June 3, 2009, 29(22):7124-7136; doi:10.1523/JNEUROSCI.1090-09.2009

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

Atheir I. Abbas,^1 * Prem N. Yadav,^2 * Wei-Dong Yao,^7,8,9,10 Margaret I. Arbuckle,¹¹ Seth G. N. Grant,^11,12 Marc G. Caron,^7,8,9 and Bryan L. Roth^1,2,3,4,5,6

¹Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, Departments of ²Pharmacology, ³Medicinal Chemistry, and ⁴Psychiatry, ⁵Lineberger Cancer Center, and ⁶National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina, Chapel Hill, North Carolina 27599, Departments of ⁷Cell Biology, ⁸Medicine, and ⁹Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, ¹⁰Department of Psychiatry, Division of Neurosciences, New England Primate Research Center, Harvard Medical School, Boston, Massachusetts 02115, ¹¹Division of Neuroscience, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom, and ¹²Genes to Cognition Programme, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom

Correspondence should be addressed to Dr. Bryan L. Roth, Department of Pharmacology, University of North Carolina, 4009 Genetics Medicine Building, CB#7365, Chapel Hill, NC 27599-7365. Email: bryan_roth{at}med.unc.edu

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.

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Received March 5, 2009; revised April 13, 2009; accepted April 23, 2009.

Correspondence should be addressed to Dr. Bryan L. Roth, Department of Pharmacology, University of North Carolina, 4009 Genetics Medicine Building, CB#7365, Chapel Hill, NC 27599-7365. Email: bryan_roth{at}med.unc.edu

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