Dependence of hippocampal function on ERRγ-regulated mitochondrial metabolism

Liming Pei*, Yangling Mu, Mathias Leblanc, William Alaynick, Grant D. Barish, Matthew Pankratz, Tiffany W. Tseng, Samantha Kaufman, Christopher Liddle, Ruth T. Yu, Michael Downes, Samuel L. Pfaff, Johan Auwerx, Fred H. Gage, Ronald M. Evans

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


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 (ERRγ) orchestrates the expression of a distinct neural gene network promoting mitochondrial oxidative metabolism that reflects the extraordinary neuronal dependence on glucose. ERRγ-/- neurons exhibit decreased metabolic capacity. Impairment of long-term potentiation (LTP) in ERRγ-/- hippocampal slices can be fully rescued by the mitochondrial OxPhos substrate pyruvate, functionally linking the ERRγ knockout metabolic phenotype and memory formation. Consistent with this notion, mice lacking neuronal ERRγ in cerebral cortex and hippocampus exhibit defects in spatial learning and memory. These findings implicate neuronal ERRγ in the metabolic adaptations required for memory formation.

Original languageEnglish (US)
Pages (from-to)628-636
Number of pages9
JournalCell Metabolism
Issue number4
StatePublished - Apr 7 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Physiology
  • Cell Biology


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