Understanding how deviations in postnatal hippocampal neurogenesis and circuit activity contribute to bipolar disorder with patient-derived pluripotent stem cells
The brain is vulnerable to many disorders that can strike at every stage of life. Bipolar disorder (BD) is a chronic and disabling neuropsychiatric condition that affects 1 in 50 Canadian adults. Like other mental illnesses, BD poses a heavy burden on society due to the cost of care and treatment, and the limited efficacy and/or serious side effects of available drug treatments. Above all, current therapies target only the symptoms and not the underlying cause of BD, which remain poorly understood. This project aims to overcome that problem by testing the idea that dysregulation of a store-operated calcium entry (SOCE) in precursor neurons contributes to the development of BD by affecting the growth and maturation of new neurons in the hippocampus after birth. We expect that our efforts could help identify new targets for the development of better pharmacological therapies. Specifically, our team recently discovered that induced pluripotent stem cell models prepared from BD patients exhibit striking deficits in calcium signaling mediated by SOCE, which we found affects the growth and development of neurons as a result. Using a unique combination of molecular and cellular methodologies, combined with brain network electrical activity recordings, we now propose to develop a unique line of investigation in BD research that will examine in detail the effect of this abnormal calcium signaling on the activity of the hippocampus, an area of the brain that has been implicated in mood regulation and the etiology of BD. Ultimately, our research will establish if SOCE dysfunction represents a disease mechanism for BD. Finally, in addition to advancing our knowledge of BD biology, the proposed research offers an excellent opportunity to establish a new cellular, systems, and behavioural assay platform for leading-edge research for other neuropsychiatric disorders that have been linked to problems in hippocampus function.
Jasmin Lalonde , University of Guelph
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The Azrieli Foundation