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

Abstract

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.

A novel role for phospholamban in the thalamic reticular nucleus

“…Indeed, compelling evidence suggests that SERCA plays a critical role in brain physiology and pathophysiology; SERCA2 dysregulation has been associated with several neuropsychiatric disorders, including schizophrenia, bipolar disorder, cerebral ischemia, alcoholism, as well as Alzheimer’s and Parkinson’s diseases (for review see 17 , 62 ). Interestingly, recent studies from our group have revealed that chronic pharmacological stimulation of SERCA induces anxiety- and depressive-like behaviors, memory deficits, as well as sustained brain region-specific noradrenergic and serotonergic neurochemical alterations in mice, further highlighting the importance of dissecting the neurobiological implications of SERCA2-dependent Ca 2+ regulatory mechanisms in the brain 51 , 39 .…”

“…Impulsivity and attention were assessed using the 5-CSRTT in a 9-hole operant chamber using protocols provided by Lafayette Instrument Co (Lafayette Instrument Co., IN, USA) and based on previous studies from our lab and others 51 – 53 . Male and female control and cKO were housed throughout a reverse 24/h light/dark cycle, and all testing was performed during dark hours.…”