Neurons utilize mitochondrial oxidative phosphorylation (OxPhos) to generate energy essential for survival, function, and behavioral output. Unlike most cells that burn both fat and sugar, neurons only burn sugar. Despite its importance, how neurons meet the increased energy demands of complex behaviors such as learning and memory is poorly understood. Here we show that the estrogen-related receptor gamma (ERR gamma) orchestrates the expression of a distinct neural gene network promoting mitochondrial oxidative metabolism that reflects the extraordinary neuronal dependence on glucose. ERR gamma(-/-) neurons exhibit decreased metabolic capacity. Impairment of long-term potentiation (LTP) in ERR gamma(-/-) hippocampal slices can be fully rescued by the mitochondrial OxPhos substrate pyruvate, functionally linking the ERR gamma knockout metabolic phenotype and memory formation. Consistent with this notion, mice lacking neuronal ERR gamma in cerebral cortex and hippocampus exhibit defects in spatial learning and memory. These findings implicate neuronal ERR gamma in the metabolic adaptations required for memory formation.
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