Genetic Manipulation of the Murine Choline Transporter

Abstract

Neuroscience

Dissertation under the direction of Professor Randy D. Blakely

This dissertation is focused on the function and regulation of the choline transporter (CHT). I used CHT heterozygous and homozygous mice, and combined biochemical, pharmacological, and behavioral approaches to test the hypothesis that CHT is essential for acetylcholine (ACh) turnover and behaviors dependent on cholinergic signaling in vivo. My work demonstrates that CHT homozygous knockout mice are born with wild type levels of ACh, but are unable to sustain ACh synthesis and release under high demand for ACh turnover. CHT heterozygosity, on the other hand, results in diminished pools of ACh. Consequenly, focused behavioral and pharmacological challenges reveal that CHT heterozygous mice are vulnerable to sustained demands on cholinergically-supported behaviors. In summary, my thesis work provides new insights into the role of CHT in the maintenance of ACh turnover and cholinergic neurotransmission. The CHT heterozygous mice constitute a new animal model of cholinergic dysfunction, and offer opportunities for further studies of CHT function and regulation, with the eventual goal of manipulating CHT in disorders of cholinergic origin.

Approved: Professor Randy D. Blakely, May 2008