Investigating novel sarco/endoplasmic reticulum calcium atpase (SERCA)-dependent mechanisms involved in mouse behavior

Date of Award

2021

Degree Name

Ph.D. in Biology

Department

Department of Biology

Advisor/Chair

Pothitos Pitychoutis

Abstract

Calcium (Ca2+) ions are critical regulators of neural cell function and survival, while disruption of Ca2+ handling in the brain has been associated with severe neuropsychiatric and neurodevelopmental disorders. Given the innate complexity of neural cell function, an intricate network of Ca2+-signaling regulators is involved in maintaining intracellular Ca2+ homeostasis. Amongst all, the Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA) is considered the gatekeeper of intracellular Ca2+ homeostasis. SERCA pumps are integral membrane proteins of the sarco/endoplasmic reticulum facilitating the flux of Ca2+ ions from the cytosol into the ER lumen. SERCA2 is the prominent SERCA isoform being ubiquitously expressed in the brain. Most importantly, SERCA-dependent dysfunction of Ca2+ homeostasis has been associated with several debilitating brain disorders; this highlights the importance of understanding the intricate SERCA-dependent regulatory mechanisms involved in brain physiology and pathophysiology. In the current Ph.D. dissertation, we sought to investigate the effects of direct and indirect regulation of SERCA on mouse behavior. In the context of a dose-dependent, sychopharmacological study we first assessed the behavioral and neurochemical consequences of acute and chronic pharmacological SERCA stimulation in male and female mice. Additionally, we used a constitutive, global knockout mouse model approach to investigate the role of a novel SERCA regulator in the brain. Specifically, we assessed how ablation of this molecular player may affect different aspects of mouse behavior (i.e., locomotor activity, sleep architecture, learning and memory), and we generated a novel conditional transgenic mouse model that will serve as a tool to further dissect the role of this novel regulator in the brain physiology and pathophysiology. Taken together, our findings highlight an important role for SERCA in regulating critical neurobehavioral processes in mice. Importantly, gaining insights into the regulation of Ca2+ homeostasis in the brain may hold great promise for the discovery of new pharmacotherapeutic targets for the treatment of debilitating brain disorders.

Keywords

Biology, calcium, SERCA, CDN1163, mouse behavior

Rights Statement

Copyright © 2021, author.

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