A Novel Role for Phospholamban and the Sarco/Endoplasmic Reticulum Calcium ATPase in the Brain and Behavior

Date of Award

5-5-2024

Degree Name

Ph.D. in Biology

Department

Department of Biology

Advisor/Chair

Pothitos Pitychoutis

Abstract

Calcium (Ca2+) ions play a vital role as an intracellular second messenger for a wide variety of cellular processes including cell growth and proliferation, metabolism, and gene expression. Neurons are no exception to this, as intracellular Ca2+ homeostasis impacts processes such as long-term potentiation, synaptic transmission, and firing patterns. Not surprisingly, neurons express a wide range of Ca2+ regulatory proteins; of these, the sarco/endoplasmic reticulum Ca2+ ATP-ase 2 (SERCA) functions as the primary Ca2+ sequestration mechanism into the endoplasmic reticulum (ER), a major intracellular Ca2+ store. Phospholamban (PLN) is a small phosphoprotein and critical SERCA2 inhibitor with a well-established role in the heart that our group has found to also be expressed in the thalamic reticular nucleus (TRN) of the mouse brain. Indeed, proper regulation of the SERCA2 is critical to neuronal health and functioning. Thus, understanding the precise role of the PLN/SERCA2 pathway along with its regulatory networks is critical to understand its implication in the pathophysiology of neurodevelopmental, neurodegenerative and neuropsychiatric disorders. In the context of this Ph.D. dissertation, we sought to elucidate the role of both SERCA2 and PLN in brain function and behavior. To this aim, we employed the novel pharmacological SERCA activator CDN1163 to assess the behavioral effects of chronic SERCA activation on cognitive processes and executive functioning in mice. Further, we employed genetic mouse knockout approaches to investigate the role of PLN in the TRN of the adult mouse brain. Specifically, we employed a novel conditional knockout mouse model in which PLN is selectively ablated in TRN neurons in order to understand the role of PLN in behaviorsthat map onto thalamic reticular circuits, including locomotor activity, sleep, and executive functioning. Overall, the findings of the current Ph.D. dissertation help define novel central PLN/SERCA2- dependent Ca2+ circuits with marked impact on behavioral processes.

Keywords

Calcium, SERCA, Phospholamban, CDN1163, thalamic reticular nucleus, TRN

Rights Statement

Copyright 2024, author

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