Grant: Project Grant

Bipolar Disorder (BD) is the sixth leading cause of disability worldwide. Mitochondria, the powerhouse of the cell, plays a central role in the pathophysiology of BD. One plausible hypothesis for BD prevalence is failure of mitochondrial function to support adequate neurotransmission and synaptic plasticity, potentially affecting mood regulation, memory, and executive function. We propose a novel and sophisticated project to answer the following question: "Is mitochondrial function the cause of neurotransmission changes in BD?" To accomplish this, we aim (1) to examine the impact of mitochondrial genetics on mitochondrial function using induced pluripotent stem cell- (iPSC-) derived neuronal progenitor cells (NPCs) and iPSC-derived neurons from families with diagnosis of BD and mitochondrial disease; (2) to determine the effect of mitochondrial dysfunction on neurotransmission phenotypes using 3D brain organoids derived from family members and 3D brain organoids derived from human embryonic stem cells (hESC) knocked down for NDUFS7 (an essential mitochondrial complex I protein demonstrated to be downregulated in BD); and (3) to test whether lithium treatment (a classical mood stabilizer) restores mitochondrial function and ultimately neurotransmission, using iPSC-derived neurons and 3D brain organoids developed for Aim 1 and 2. The results of this project will give better insight into BD brain pathophysiology and whether mitochondrial dysfunction plays a key role in dysregulated neurotransmission in bipolar disorder. Beyond this, there is potential for discovery of novel drug targets aimed at restoring both mitochondrial function and neurotransmission, which will substantially improve the lives of Canadians affected by either BD or mitochondrial disease.