ERR? links adaptive neuronal metabolism to spatial learning and memory [ChIP-Seq]

Neurons utilize glucose to generate adenosine triphosphate (ATP) essential for their survival, excitability and synaptic signaling, as well as initiating changes in neuronal structure and function. Defects in oxidative metabolism and mitochondria functions are also associated with aging and diverse human neurological diseases1-4. While neurons are known to adapt their metabolism to meet the increased energy demands of complex behaviors such as learning and memory, the molecular underpinnings regulating this process remain poorly understood4-6. Here we show that the orphan nuclear receptor estrogen related receptor gamma (ERR?) becomes highly expressed during retinoic-acid induced neurogenesis and is widely expressed in neuronal nuclei throughout the brain. Mechanistically, we show that ERR? directly orchestrates the expression of networks of genes involved in mitochondrial oxidative phosphorylation and energy generation in neurons. The importance of this regulation is evidenced by decreased adaptive metabolic capacity in cultured neurons lacking ERR?, and reduced long-term potentiation (LTP) in ERR?-/- hippocampal slices. Notably, the defect in LTP was rescued by the metabolic intermediate pyruvate, functionally linking the ERR? knockout metabolic phenotype and memory formation. Consistent with this notion, mice lacking neuronal ERR? exhibit defects in spatial learning and memory. These findings implicate ERR? in the metabolic adaptations required for long-term memory formation. Overall design: We used ChIP-Seq analysis to determine the genome-wide binding of ERR? in neurons derived from ES cells.