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.

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.

Sex Differences in the Temporal Neuromolecular and Synaptogenic Effects of the Rapid-acting Antidepressant Drug Ketamine in the Mouse Brain.

Preclinical evidence suggests that ketamine's rapid and sustained antidepressant actions are due to the induction of synaptogenesis in the medial prefrontal cortex (mPFC) and the hippocampus (HIPP), two brain regions implicated in the pathophysiology of major depression. However, research on the neurobiological effects of ketamine has focused almost exclusively on males. Findings from our group and others indicate that female rodents are more reactive to ketamine's antidepressant effects, since they respond to lower doses in antidepressant-predictive behavioral models. The sex-dependent mechanisms that mediate the antidepressant effects of ketamine in the female brain are elusive. Herein, we assessed the neurobiological effects of a single ketamine dose (10 mg/kg; previously shown to induce rapid and sustained antidepressant-like effects in mice of both sexes), on glutamate release in the mPFC, as well as on the expression of synaptic plasticity markers, and spine density in the mPFC and the HIPP of C57BL/6J mice. Our data revealed that ketamine induced a sex-specific "glutamate burst" in the male mPFC. Ketamine activated the mammalian target of rapamycin complex 1 (mTORC1) pathway in prefrontocortical synaptoneurosomes, and enhanced spine formation in the male mPFC and HIPP. In females, ketamine induced a sustained increase in hippocampal spine density. Overall, these data exposed a sharp sex difference in the synaptogenic response to ketamine in stress-naïve mice, and further suggest that the mPFC may play a more important role in mediating the antidepressant effects of the drug in males, while the HIPP may be more important for females.

The SERCA2: A Gatekeeper of Neuronal Calcium Homeostasis in the Brain.

Calcium (Ca2+) ions are prominent cell signaling regulators that carry information for a variety of cellular processes and are critical for neuronal survival and function. Furthermore, Ca2+ acts as a prominent second messenger that modulates divergent intracellular cascades in the nerve cells. Therefore, nerve cells have developed intricate Ca2+ signaling pathways to couple the Ca2+ signal to their biochemical machinery. Notably, intracellular Ca2+ homeostasis greatly relies on the rapid redistribution of Ca2+ ions into the diverse subcellular organelles which serve as Ca2+ stores, including the endoplasmic reticulum (ER). It is well established that Ca2+ released into the neuronal cytoplasm is pumped back into the ER by the sarco-/ER Ca2+ ATPase 2 (SERCA2), a P-type ion-motive ATPase that resides on the ER membrane. Even though the SERCA2 is constitutively expressed in nerve cells, its precise role in brain physiology and pathophysiology is not well-characterized. Intriguingly, SERCA2-dependent Ca2+ dysregulation has been implicated in several disorders that affect cognitive function, including Darier's disease, schizophrenia, Alzheimer's disease, and cerebral ischemia. The current review summarizes knowledge on the expression pattern of the different SERCA2 isoforms in the nervous system, and further discusses evidence of SERCA2 dysregulation in various neuropsychiatric disorders. To the best of our knowledge, this is the first literature review that specifically highlights the critical role of the SERCA2 in the brain. Advancing knowledge on the role of SERCA2 in maintaining neuronal Ca2+ homeostasis may ultimately lead to the development of safer and more effective pharmacotherapies to combat debilitating neuropsychiatric disorders.

Lipopolysaccharide administration induces sex-dependent behavioural and serotonergic neurochemical signatures in mice.

Challenging the innate immune machinery with the pro-inflammatory agent lipopolysaccharide (LPS) results in the development of a sickness syndrome characterized by numerous depressive-like behavioural and physiological manifestations, most of which overlap with the clinical symptoms of major depression. Although women are known to mount stronger pro-inflammatory responses during infections and being at higher risk to develop depressive disorders compared to men, the vast majority of experimental studies investigating the neurobiological effects of LPS administration have been conducted in males. Herein, we investigated the behavioural effects of LPS administration (0.83mg/kg) in male and female C57BL/6J mice subjected to tests screening for alterations in locomotor activity (open field test), anorexia (food consumption), anhedonia (sucrose preference test), behavioural despair (forced swim test) and grooming behaviour (splash-test). We further mapped the brain's serotonergic and dopaminergic activity in five limbic brain regions implicated in the pathophysiology of major depression (i.e., prefrontal cortex, hippocampus, striatum, amygdala, and hypothalamus) at two critical time-points post-LPS treatment; at 6h when depression of behavioural activity is maximal, and at 24h when depressive-like symptoms develop independently of obvious locomotor performance impairments associated with acute LPS administration. Our findings indicate that the two sexes present with differential behavioural sensitivity to this immune stressor, as impairment of grooming behaviour in the splash test was more persistent in female mice, and anorexia lasted longer in their male counterparts. Notably, LPS affects the brain's serotonergic neurochemistry in a sex-specific manner, as it induced sustained serotonergic hyperactivity in females at 24h post-LPS administration in all the brain regions examined. Moreover, the kinetics of dopaminergic activation appeared to be sex-differentiated upon LPS challenge. Given the higher prevalence of affective disorders in women, a focus of basic science on sex differences that underlie neuroinflammatory processes is imperative in order to elucidate the neuroimmunological substrate of major depression.