Mitochondrial diversity as a regulator of cell- and circuit-specific functions

PROJECT SUMMARY/ABSTRACT The goal of this research proposal is to gain mechanistic insight into how the distinct mitochondrial properties of hippocampal CA2 neurons contribute to their function in learning and memory. Area CA2 is an understudied region of the hippocampus that has recently gained attention due to its unique capacity to encode social infor- mation. However, the molecular mechanisms underlying the essential processes in CA2 required for its function in social memory are unknown. This proposal builds upon our recent finding that hippocampal CA2 pyramidal neurons have molecularly and functionally distinct mitochondria compared with neighboring CA1 neurons. Spe- cifically, our data point to differences in mitochondrial calcium uptake and bioenergetics, which we propose con- fer unique synaptic and circuit properties essential to CA2 function. It remains unclear how mitochondrial diversity influences cell- and circuit-specific functions. Incomplete knowledge of the impact of mitochondrial heterogeneity is a key obstacle impeding our understanding of mito- chondrial function in brain health and disease. The specific aims of this grant use innovative tools to visualize and modify molecularly distinct mitochondria to investigate the role of mitochondrial calcium uptake in driving bioenergetics, mitochondrial localization, and plasticity in the hippocampal circuit. We propose that mitochon- drial diversity might be a key node in the regulation of cell specific properties underlying neural function, and may influence region-specific differences in disease pathology. Completion of this project will advance our un- derstanding of the basic cell biological mechanisms regulating a cell type important for social memory and will identify novel therapeutic candidates for disorders with social deficits, such as schizophrenia and autism. The general principles learned about mitochondrial heterogeneity from this proposal will be broadly applicable to other brain areas and organ systems.