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PSD-95 Regulates Serotonin Receptor Function in vivo

Abbas, Atheir Ibrahim
http://rave.ohiolink.edu/etdc/view?acc_num=case1237990096

Abstract Details

2009, Doctor of Philosophy, Case Western Reserve University, Biochemistry.
The 5-hydroxytryptamine 2A (5-HT2A) receptor, a target for hallucinogens and some antipsychotics, is thought to play a prominent role in regulating mood, perception, and cognition. The closely related 5-hydroxytryptamine 2C (5-HT2C)receptor is also thought to be involved in a number of central nervous system processes including mood and temperature regulation. Due to the behavioral effects that result from activation and blockade of 5-HT2A and 5-HT2C receptors, it has been suggested that these receptors can modulate glutamatergic neurotransmission, though the biochemical links between the metabotropic serotonin and ionotropic glutamate systems have remained a mystery. In the studies presented herein we show that the postsynaptic PDZ domain-containing scaffolding protein postsynaptic density protein of 95kDa (PSD-95), a 5-HT2A/2C-interacting protein, is an important biochemical link between the serotonin and glutamate systems. We show that, in the absence of PSD-95 in vivo, 5-HT2A and 5-HT2C receptor expression is reduced due to an increase in the rate of receptor turnover. We also provide evidence that targeting to the appropriate apical dendritic compartment is impaired in neurons cultured from PSD-95 knockout mice, and that lentiviral addback of PSD-95 to knockout neurons rescues targeting. We also examine signaling at both the biochemical and behavioral level. With respect to the 5-HT2C receptor, we show that the ability of a 5-HT2C agonist to induce c-fos, a marker of neuronal activation, is greatly reduced in the absence of PSD-95. We also present data showing that 5-HT2A-mediated hallucinogen-induced head twitch is also reduced in the absence of PSD-95. Finally, we provide evidence that clozapine, which is thought to correct the abnormalities in glutamatergic neurontransmission seen in some animal models of psychosis via a 5-HT2A-dependent mechanism, is unable to exert its therapeutic efficacy in PSD-95 knockout mice. Together the data presented herein provide the first biochemical link between the metabotropic serotonin and ionotropic glutamate systems. Our studies also suggest that this link is relevant not only with respect to the regulation of 5-HT2A and 5-HT2C receptor function, but also with respect to hallucinogen action and the neurochemistry underlying psychosis.
Bryan Roth, M.D., Ph.D. (Advisor)
George Dubyak, Ph.D. (Committee Member)
Vernon Anderson, Ph.D. (Committee Chair)
William Merrick, Ph.D. (Committee Member)
Martin Snider, Ph.D. (Committee Member)
Paul Ernsberger, Ph.D. (Committee Member)
160 p.
Biochemistry; Pharmacology
5-HT2A; 5-HT2C; PSD-95; hallucinogen; antipsychotic; clozapine; serotonin receptors

Recommended Citations

Citations

  • Abbas, A. I. (2009). PSD-95 Regulates Serotonin Receptor Function in vivo [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1237990096

    APA Style (7th edition)

  • Abbas, Atheir. PSD-95 Regulates Serotonin Receptor Function in vivo. 2009. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1237990096.

    MLA Style (8th edition)

  • Abbas, Atheir. "PSD-95 Regulates Serotonin Receptor Function in vivo." Doctoral dissertation, Case Western Reserve University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1237990096

    Chicago Manual of Style (17th edition)

case1237990096
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© 2009, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.