title: Dependence of hippocampal function on ERRγ-regulated mitochondrial metabolism.
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.
authors: Center for Mitochondrial and Epigenomic Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: lpei@mail.med.upenn.edu.
authors: Liming
authors: L
authors: Pei
authors: Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors: Yangling
authors: Y
authors: Mu
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors: Mathias
authors: M
authors: Leblanc
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors: William
authors: W
authors: Alaynick
authors: Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors: Grant D
authors: GD
authors: Barish
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors: Matthew
authors: M
authors: Pankratz
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors: Tiffany W
authors: TW
authors: Tseng
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors: Samantha
authors: S
authors: Kaufman
authors: Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, New South Wales 2145, Australia.
authors: Christopher
authors: C
authors: Liddle
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors: Ruth T
authors: RT
authors: Yu
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors: Michael
authors: M
authors: Downes
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors: Samuel L
authors: SL
authors: Pfaff
authors: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors: Johan
authors: J
authors: Auwerx
authors: Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors: Fred H
authors: FH
authors: Gage
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: evans@salk.edu.
authors: Ronald M
authors: RM
authors: Evans
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D047369:Chromatin Immunoprecipitation; D005697:Galactosides; D055786:Gene Knockout Techniques; D006019:Glycolysis / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology*; D007211:Indoles; D017774:Long-Term Potentiation / Q000502:physiology*; D008568:Memory / Q000502:physiology; D051379:Mice; D046228:Microarray Analysis; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D019289:Pyruvic Acid; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000378:metabolism*; D065853:Spatial Learning / Q000502:physiology
chemical_list: C490916:Esrrg protein, mouse; D005697:Galactosides; D007211:Indoles; D011960:Receptors, Estrogen; D019289:Pyruvic Acid; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside