Nature Neuroscience 9, 381 - 388 (2006)
Published online: 19 February 2006; | doi:10.1038/nn1656
Ghrelin controls hippocampal spine synapse density and memory performanceSabrina Diano1, 9, Susan A Farr2, 3, Stephen C Benoit4, Ewan C McNay5, Ivaldo da Silva1, Balazs Horvath1, F Spencer Gaskin2, 3, Naoko Nonaka2, 3, Laura B Jaeger2, 3, William A Banks2, 3, John E Morley2, 3, Shirly Pinto6, Robert S Sherwin5, Lin Xu7, Kelvin A Yamada7, Mark W Sleeman8, Matthias H Tschöp4
& Tamas L Horvath1, 9, 101
Department of Obstetrics and Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA. 2
Geriatric Research Education and Clinical Center (GRECC), VA Medical Center, St. Louis, Missouri 63106, USA. 3
Department of Internal Medicine, Division of Geriatric Medicine, St. Louis University School of Medicine, St. Louis, Missouri 63106, USA. 4
Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio 45237, USA. 5
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA. 6
Department of Molecular Genetics, Howard Hughes Medical Institute, Rockefeller University, New York, New York 10021, USA. 7
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. 8
Regeneron Pharmaceuticals Inc., Tarrytown, New York 10591, USA. 9
Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. 10
Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Correspondence should be addressed to Tamas L Horvath tamas.horvath@yale.edu The gut hormone and neuropeptide ghrelin affects energy balance and growth hormone release through hypothalamic action that involves synaptic plasticity in the melanocortin system. Ghrelin binding is also present in other brain areas, including the telencephalon, where its function remains elusive. Here we report that circulating ghrelin enters the hippocampus and binds to neurons of the hippocampal formation, where it promotes dendritic spine synapse formation and generation of long-term potentiation. These ghrelin-induced synaptic changes are paralleled by enhanced spatial learning and memory. Targeted disruption of the gene that encodes ghrelin resulted in decreased numbers of spine synapses in the CA1 region and impaired performance of mice in behavioral memory testing, both of which were rapidly reversed by ghrelin administration. Our observations reveal an endogenous function of ghrelin that links metabolic control with higher brain functions and suggest novel therapeutic strategies to enhance learning and memory processes.
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