Date of Award

Winter 2019

Project Type

Thesis

Program or Major

Genetics

Degree Name

Master of Science

First Advisor

Arturo Andrade

Second Advisor

Sergios Charntikov

Third Advisor

Xuanmao Chen

Abstract

CaV2.2 (N-type) channel is a presynaptic channel that enables calcium influx into axon terminals, thereby playing a vital role in coupling action potentials to neurotransmitter release in the central and peripheral nervous systems. In vitro studies of CaV2.2 show that the channel directly modulates levels of the monoamines including dopamine, serotonin, and norepinephrine. Further, CaV2.2-null mice exhibit heightened aggression and hyperlocomotion linked to aberrant dopamine and serotonin function. All these studies suggest that CaV2.2 plays a pivotal role in monoaminergic function. CaV2.2 contains an alternatively spliced exon, e18a, which is either included (+18a-CaV2.2) or removed (Δ18a-Ca¬V2.2) from the channel and alters calcium influx through CaV2.2 in vitro. +18a-CaV2.2 is expressed as the dominant isoform in midbrain monoaminergic areas including the substantia nigra, the ventral tegmental area, the dorsal raphe nuclei, and the locus coeruleus, as well as sympathetic system in the periphery. Its selective expression and modulation of CaV2.2 calcium current suggest that e18a could play a role in modulating midbrain monoaminergic communication and function. To study the potential in vivo effects of e18a, we utilized an e18a mouse where this exon was removed (Δ18a-only) and a battery of behavioral tests to assess monoamine function. We found that mice lacking 18a show deficits in their responses to inescapable stress. We have also demonstrated that these defects are not attributed to alterations in basal exploratory behavior, appetitive reward, or nociception. Our results point at a novel role of CaV2.2 alternative splicing in stress responses and a possible link to monoamine function.

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