title: Metabolic regulation of neuronal plasticity by the energy sensor AMPK.
abstract: Long Term Potentiation (LTP) is a leading candidate mechanism for learning and memory and is also thought to play a role in the progression of seizures to intractable epilepsy. Maintenance of LTP requires RNA transcription, protein translation and signaling through the mammalian Target of Rapamycin (mTOR) pathway. In peripheral tissue, the energy sensor AMP-activated Protein Kinase (AMPK) negatively regulates the mTOR cascade upon glycolytic inhibition and cellular energy stress. We recently demonstrated that the glycolytic inhibitor 2-deoxy-D-glucose (2DG) alters plasticity to retard epileptogenesis in the kindling model of epilepsy. Reduced kindling progression was associated with increased recruitment of the nuclear metabolic sensor CtBP to NRSF at the BDNF promoter. Given that energy metabolism controls mTOR through AMPK in peripheral tissue and the role of mTOR in LTP in neurons, we asked whether energy metabolism and AMPK control LTP. Using a combination of biochemical approaches and field-recordings in mouse hippocampal slices, we show that the master regulator of energy homeostasis, AMPK couples energy metabolism to LTP expression. Administration of the glycolytic inhibitor 2-deoxy-D-glucose (2DG) or the mitochondrial toxin and anti-Type II Diabetes drug, metformin, or AMP mimetic AICAR results in activation of AMPK, repression of the mTOR pathway and prevents maintenance of Late-Phase LTP (L-LTP). Inhibition of AMPK by either compound-C or the ATP mimetic ara-A rescues the suppression of L-LTP by energy stress. We also show that enhanced LTP via AMPK inhibition requires mTOR signaling. These results directly link energy metabolism to plasticity in the mammalian brain and demonstrate that AMPK is a modulator of LTP. Our work opens up the possibility of using modulators of energy metabolism to control neuronal plasticity in diseases and conditions of aberrant plasticity such as epilepsy.
authors.affiliation: Department of Neurology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Wyatt B
authors.initials: WB
authors.lastname: Potter
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: O'Riordan
authors.forename: David
authors.initials: D
authors.lastname: Barnett
authors.forename: Susan M K
authors.initials: SM
authors.lastname: Osting
authors.forename: Matthew
authors.initials: M
authors.lastname: Wagoner
authors.forename: Corinna
authors.initials: C
authors.lastname: Burger
authors.forename: Avtar
authors.initials: A
authors.lastname: Roopra
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D015153:Blotting, Western; D003847:Deoxyglucose / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D006624:Hippocampus / Q000201:enzymology / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D009473:Neuronal Plasticity / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D014740:Vidarabine / Q000494:pharmacology
chemical_list: D000963:Antimetabolites; D007004:Hypoglycemic Agents; D047908:Intracellular Signaling Peptides and Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D012265:Ribonucleotides; C516138:dorsomorphin; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D003847:Deoxyglucose; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D014740:Vidarabine