A novel role for phospholamban in the thalamic reticular nucleus.

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.

A Novel Role for Phospholamban in the Thalamic Reticular Nucleus.

The thalamic reticular nucleus (TRN) is a critical brain region that greatly influences vital neurobehavioral processes, including executive functioning and the generation of sleep rhythms. Recently, TRN dysfunction was suggested to underlie hyperactivity, attention deficits, and sleep disturbances observed across various devastating neurodevelopmental disorders, including autism, schizophrenia and attention-deficit/hyperactivity disorder (ADHD). Notably, a highly specialized sarco- endoplasmic reticulum calcium (Ca 2+ ) ATPase 2 (SERCA2)-dependent Ca 2+ signaling network operates in the dendrites of TRN neurons to regulate their high-frequency bursting activity. Phospholamban (PLN) is a prominent regulator of the SERCA2 with an established role in maintaining Ca 2+ homeostasis in the heart; although the interaction of PLN with SERCA2 has been largely regarded as cardiac-specific, our findings challenge this view and suggest that the role of PLN extends beyond the cardiovascular system to impact brain function. Specifically, we found PLN to be expressed in the TRN neurons of the adult mouse brain and utilized global constitutive and innovative conditional genetic mouse models, in combination with 5-choice serial reaction time task (5-CSRTT) and electroencephalography (EEG)-based somnography to assess the role of PLN in regulating executive functioning and sleep, two complex behaviors that map onto thalamic reticular circuits. Overall, the results of the present study show that perturbed PLN function in the TRN results in aberrant thalamic reticular behavioral phenotypes in mice (i.e., hyperactivity, impulsivity and sleep deficits) and support a novel role for PLN as a critical regulator of the SERCA2 in the thalamic reticular neurocircuitry.

Chronic pharmacological activation of SERCA with CDN1163 affects spatial cognitive flexibility but not attention and impulsivity in mice.

Intracellular calcium (Ca2+) homeostasis is critical for many neural processes, including learning, memory and synaptic plasticity. The sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) is among the key regulators that preserve Ca2+ homeostasis in neurons. SERCAs comprise a set of ubiquitously expressed Ca2+ pumps that primarily function to sequester cytosolic Ca2+ into endoplasmic reticular stores. As SERCA has been implicated in the neurobiology of several neuropsychiatric and neurodegenerative diseases, pharmacological harnessing of its function is critical in understanding SERCA's role in brain physiology and pathophysiology. In the current study, we employed the Morris water maze and 5-choice serial reaction time task (5-CSRTT) to investigate the effects of chronic pharmacological activation of SERCA, using the small allosteric SERCA activator CDN1163, on spatial learning and memory, and executive functioning in naive C57BL/6J mice. Our data show that chronic pharmacological SERCA activation with CDN1163 (20 mg/kg) selectively impairs spatial cognitive flexibility and reversal learning in the Morris water maze while leaving executive functions such as attention and impulsivity intact. Present findings contribute to the growing field of the role of SERCA function in the brain and behavior and expand current knowledge on the use of the small allosteric activator CDN1163 as an investigational tool to study the role of SERCA in regulating neurobehavioral processes and as a potential therapeutic candidate for debilitating brain disorders.

Insights into the role of intracellular calcium signaling in the neurobiology of neurodevelopmental disorders.

Calcium (Ca2+) comprises a critical ionic second messenger in the central nervous system that is under the control of a wide array of regulatory mechanisms, including organellar Ca2+ stores, membrane channels and pumps, and intracellular Ca2+-binding proteins. Not surprisingly, disturbances in Ca2+ homeostasis have been linked to neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. However, aberrations in Ca2+ homeostasis have also been implicated in neuropsychiatric disorders with a strong neurodevelopmental component including autism spectrum disorder (ASD) attention-deficit hyperactivity disorder (ADHD) and schizophrenia (SCZ). While plasma membrane Ca2+ channels and synaptic Ca2+-binding proteins have been extensively studied, increasing evidence suggests a prominent role for intracellular Ca2+ stores, such as the endoplasmic reticulum (ER), in aberrant neurodevelopment. In the context of the current mini-review, we discuss recent findings implicating critical intracellular Ca2+-handling regulators such as the sarco-ER Ca2+ ATPase 2 (SERCA2), ryanodine receptors (RyRs), inositol triphosphate receptors (IP3Rs), and parvalbumin (PVALB), in the emergence of ASD, SCZ, and ADHD.

A Role for SERCA Pumps in the Neurobiology of Neuropsychiatric and Neurodegenerative Disorders.

Calcium (Ca2+) is a fundamental regulator of cell fate and intracellular Ca2+ homeostasis is crucial for proper function of the nerve cells. Given the complexity of neurons, a constellation of mechanisms finely tunes the intracellular Ca2+ signaling. We are focusing on the sarco/endoplasmic reticulum (SR/ER) calcium (Ca2+)-ATPase (SERCA) pump, an integral ER protein. SERCA's well established role is to preserve low cytosolic Ca2+ levels ([Ca2+]cyt), by pumping free Ca2+ ions into the ER lumen, utilizing ATP hydrolysis. The SERCA pumps are encoded by three distinct genes, SERCA1-3, resulting in 12 known protein isoforms, with tissue-dependent expression patterns. Despite the well-established structure and function of the SERCA pumps, their role in the central nervous system is not clear yet. Interestingly, SERCA-mediated Ca2+ dyshomeostasis has been associated with neuropathological conditions, such as bipolar disorder, schizophrenia, Parkinson's disease and Alzheimer's disease. We summarize here current evidence suggesting a role for SERCA in the neurobiology of neuropsychiatric and neurodegenerative disorders, thus highlighting the importance of this pump in brain physiology and pathophysiology.