The serotonergic transmitter system in the mammalian brain plays important roles in various physiological functions such as mood, sexual behavior, sleep/wake cycle, blood pressure control and breathing. Serotonin mediates its effect via 5HT receptors, which are G protein coupled receptors that are expressed within 5HT neurons and their targets within the brain. The 5HT receptor, 5HT-1 A, which couple to the Gi/o signaling pathway, has been described to play major roles for anxiety and depressive behaviors. It is also and important drug target for treating many neuropsychiatric disorders. It is therefore of great importance to understand how this receptor pathway acts to modulate serotonergic tone, function, and 5HT related behaviors within the brain and in the living animals. Here, I describe a method to develop light activated GPCRs that activates the 5HT-1A specific receptor pathway. I will generate a chimeric receptor by mutating the intracellular domains of vertebrate rhodopsin by exchanging them for those of the 5HT-1A receptor. I will then characterize the function of this chimeric receptor and assess its ability to activate 5HT specific signaling in a heterologous expression system. Finally, I will assess its ability to rescue physiological phenotypes in 5HT-1A receptor knock-out mice. This chimeric receptor will enable the precise characterization of receptor pathways on neuronal function and would be a significant advance over pharmacologic manipulations, which are limited by their pharmacokinetics and can be cumbersome to use in live, intact animals. This light activated tool could be used to precisely manipulate serotonergic signaling cascades in a defined population of neurons, which will lead to a clearer understanding of normal physiology and may lead to novel therapeutics. Serotonin plays a critical role in many physiological functions and many psychiatric disorders, however the involvement of specific serotonin receptors with function and disease is largely unknown. To address this problem, I propose to develop and test light activated molecules that will activate a specific serotonin pathway in neurons.
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