Abstract
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 language | English (US) |
|---|---|
| Pages (from-to) | 628-636 |
| Number of pages | 9 |
| Journal | Cell Metabolism |
| Volume | 21 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 7 2015 |
Funding
We thank C. McDonald, M. Karunasiri, H. Juguilon, S. Andrews, M. Joens, and J. Fitzpatrick for technical and EM studies support; D. Wallace, A. Atkins, C. Perez-Garcia, R. Carney, W. Fan, J. Whyte, O. Chivatakarn, A. Levine, K. Hilde, T. Wang, R. Hernandez, Y. Kim, and M. Marchetto for helpful discussions; Z. Zhou for the PSD95 antibody; and E. Ong, C. Brondos, and S. Ganley for administrative assistance. R.M.E. is an investigator of the Howard Hughes Medical Institute at the Salk Institute for Biological Studies and March of Dimes Chair in Molecular and Developmental Biology. This work was supported by the Howard Hughes Medical Institute; NIH grants DK057978, HL105278, DK090962, and CA014195 (R.M.E.); NIMH MH090258 (F.H.G.); the Leona M. and Harry B. Helmsley Charitable Trust Grant (R.M.E. and F.H.G.); Ellison Medical Foundation (R.M.E.); Glenn Foundation for Medical Research (R.M.E.); the G. Harold & Leila Y. Mathers Charitable Foundation (F.H.G.); the JPB Foundation (F.H.G.); Annette Merrill-Smith (F.H.G.); pilot funds from the Research Institute of the Children’s Hospital of Philadelphia (CHOP); CHOP Metabolism, Nutrition and Development Research Affinity Group Pilot Grant; and Penn Medicine Neuroscience Center (PMNC) Innovative Pilot Funding Program (L.P.). L.P. conceived of the project and designed and performed most of the experiments. Y.M. performed the hippocampal LTP recordings and analyzed the data together with L.P. M.L. is a pathologist who evaluated the histology and staining results. W.A. performed some of the X-gal staining and immunostaining experiments. R.T.Y. and C.L. analyzed the ChIP-Seq and microarray data. G.D.B., M.P., T.W.T., S.K., M.D., S.L.P., and J.A. provided technical assistance, research materials, or intellectual input. R.M.E. supervised the project. L.P. and R.M.E. wrote, and F.H.G., M.D., and R.T.Y. reviewed and edited, the manuscript. L.P., R.T.Y., M.D., and R.M.E. are coinventors of a method of modulating hippocampal function and may be entitled to royalties.
ASJC Scopus subject areas
- Physiology
- Molecular Biology
- Cell Biology