candidate's abstract): This application is for a K08. While an M.D.-Ph.D. student in the laboratory of Lewis Seiden, Ph.D., and while a psychiatric resident in the laboratory of George Aghajanian, M.D., I have been impressed by potential clinical applications of understanding the neurobiology of brain 5-HT2A receptors. The 5-HT2A receptor has been implicated in the pathophysiology of schizophrenia, suicide, depression and dementia. Regulation of the 5-HT2A receptor by many antidepressant and atypical antipsychotic drugs may contribute to their therapeutic effects. Recent work in Dr. Aghajanian's laboratory has found that, 5-HT, via a novel mechanisms involving the 5-HT2A receptor, increases the release of glutamate onto atypical but not basilar dendrites of neocortical pyramidal cells. This work demonstrates that the most consistent electrophysiological effect of 5-HT2A receptor activation in the neocortex is an increase in the frequency of excitatory postsynaptic potentials/currents (EPSCs/EPSCs) that is mediated by a presynaptic action of 5-HT2A receptor activation upon glutamatergic terminals. Recent work has also indicated that potent interactions occur between 5-HT2A receptors and brain-derived neurotrophic factor (BDNF): Dr. Ronald Duman's laboratory has found that 5-HT2A agonists increase neocortical BDNF mRNA expression in an apparent activity-dependent manner and previous manner and previous work has shown that BDNF both serves as a growth factor for serotonergic neurons and increases 5-HT turnover. At this time I wish to extend by training under the mentorship of Drs. Duman, to acquire experience in molecular approaches, and Aghajanian, to consolidate my electrophysiological skills, including learning whole cell patch clamp recording. The major aims for the proposed project are: (1) to characterize receptors presynaptic to pyramidal cells that regulate 5-HT2A receptor-induced EPSCs and BDNF mRNA expression in the medial prefrontal cortex; (2) to determine the origin of glutamatergic afferents to the medial prefrontal cortex from which 5-HT2A receptor activation increases EPSCs and BDNF mRNA expression; and (3) to study the regulation of neocortical 5-HT2A receptor-induced EPSCs and BDNF expression by antidepressant and antipsychotic drugs. The overall goal of the present proposed project is to further our understanding of the specific cellular and molecular interactions of 5-HT and neurotrophins in the cortex so that ultimately this knowledge can be translated to the clinical treatment of schizophrenia, mood disorders and dementia.
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