Chronic Administration of the Novel SERCA2 Activator CDN1163 Induces Behavioral andNeurochemical Effects in Mice

The sarco/endoplasmic reticulum (SR/ER) calcium (Ca2+)-ATPase (SERCA) pump is a key regulator of intracellular Ca2+ homeostasis and subsequently essential for cell survival and function [1,2]. Neurons are no exception to this; intricate pathways involving SERCA-mediated Ca2+ signaling are implicated in brain pathophysiology. Several studies have indicated that dysregulation of SERCA pumps may be involved in the molecular mechanisms underlying debilitating brain diseases including Alzheimer’s and Parkinson’s diseases, schizophrenia, bipolar disorder, ischemia and alcoholism [1-3]. Thus, this family of P-type ATPases comprises an emerging molecular target for developing efficient pharmacotherapies. Interestingly, preclinical studies in rodents suggest that chronic pharmacological activation of SERCA2 by the quinoline derivative CDN1163 comprises a potential pharmacotherapeutic target in Alzheimer’s and Parkinson’s diseases [4-6]. As little is known about the behavioral and neurochemical consequences of CDN1163 administration, in this study we investigated the potential effects of both acute and chronic pharmacological SERCA stimulation on the behavior and monoaminergic neurotransmission of naïve C57BL/6J mice of both sexes [7].https://ecommons.udayton.edu/grad_showcase/1005/thumbnail.jp

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

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

A novel role for phospholamban in the thalamic reticular nucleus

Abstract The thalamic reticular nucleus (TRN) is a brain region that influences vital neurobehavioral processes, including executive functioning and the generation of sleep rhythms. TRN dysfunction underlies hyperactivity, attention deficits, and sleep disturbances observed across various neurodevelopmental disorders. A specialized sarco-endoplasmic reticulum calcium (Ca2+) ATPase 2 (SERCA2)-dependent Ca2+ signaling network operates in the dendrites of TRN neurons to regulate their bursting activity. Phospholamban (PLN) is a prominent regulator of SERCA2 with an established role in myocardial Ca2 +-cycling. Our findings suggest that the role of PLN extends beyond the cardiovascular system to impact brain function. Specifically, we found PLN to be expressed in TRN neurons of the adult mouse brain, and utilized global constitutive and innovative conditional genetic knockout mouse models in concert with electroencephalography (EEG)-based somnography and the 5-choice serial reaction time task (5-CSRTT) to investigate the role of PLN in sleep and executive functioning, two complex behaviors that map onto thalamic reticular circuits. The results of the present study indicate that perturbed PLN function in the TRN results in aberrant TRN-dependent phenotypes in mice (i.e., hyperactivity, impulsivity and sleep deficits) and support a novel role for PLN as a critical regulator of SERCA2 in the TRN neurocircuitry