Student Theses and Dissertations

Author

Remzi Karayol

Date of Award

2018

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Heintz Laboratory

Abstract

Anxiety and mood disorders are the most prevalent classes of mental disorders. However, current treatments for these debilitating diseases are limited due to their delayed onset of action and numerous side effects, emphasizing the need for faster acting and more efficacious therapies. Preclinical studies indicate a critical role for Serotonin Receptor 4 (5-HT4R, product of the Htr4 gene) in this direction as drugs that activate this receptor show fast-acting antidepressant-like properties. Unfortunately, 5-HT4R is widely expressed in the periphery, limiting its use as a direct therapeutic target due to various side effects. Understanding the cell type specific mechanisms of 5-HT4R function in the brain will facilitate the development of novel therapies. To dissect the function of 5-HT4R in genetically defined cell types of the hippocampus and neocortex, two regions highly implicated in emotive and cognitive function, I generated a novel Cre-dependent Htr4 knockout mouse line. Intriguingly, the loss of functional 5-HT4R specifically in the mature excitatory neurons of the hippocampus led to robust antidepressant-like behavioral, cellular and molecular responses. These phenotypes were accompanied by elevated innate anxiety levels and deficits in hippocampus-dependent memories. By slice electrophysiology, we showed that 5-HT4R was necessary for the proper excitability of dentate gyrus granule cells. To identify molecular adaptations underlying the observed changes in behavior and neuronal activity, I used the translating ribosome affinity purification (TRAP) approach combined with nextgeneration RNA sequencing to measure hippocampal region- and cell typespecific differential gene expression in the presence and absence of 5-HT4R. Analysis of these datasets revealed that the ventral and dorsal hippocampus underwent distinct molecular adaptations, and identified functionally relevant genes that may underlie these phenotypes and be potential therapeutic targets. My graduate work identified unique roles for hippocampal 5-HT4R in modulating mood, anxiety and memory. By regulating the excitability of individual neurons and relevant intracellular pathways, 5-HT4R mediates functionally distinct hippocampal circuits. Our findings suggest divergent molecular and functional roles for 5-HT4R along the dorsoventral axis of the hippocampus, and that specific cell type- or circuit-based strategies that target the 5-HT4R pathway may yield more effective antidepressant therapies.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy by Remzi Karayol June

Available for download on Sunday, November 04, 2018

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