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Ghrelin controls hippocampal spine synapse density and memory performance

Nature Neuroscience volume 9, pages 381–388 (2006)Cite this article

Abstract

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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Figure 1: Ghrelin binding in the hippocampus.
Figure 2: Peripherally administered ghrelin enters the hippocampus.
Figure 3: Effect of ghrelin on hippocampal spine synapse density.
Figure 4: Ghrelin promotes LTP generation.
Figure 5: Effects of ghrelin treatment on learning and memory performance.
Figure 6: Ghrelin's effect on memory performance of Ghr−/− mice.

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Acknowledgements

The authors thank M. Shanabrough for technical assistance and editing of the manuscript and E. Borok for the electron microscopic analyses. This work was supported by grants from the US National Institutes of Health (DK60711, DK61619, NS40525, AG22880, DK70039, NS41725, DK7386, DK70039 and AA12743) and a VA Merit Review grant.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Sabrina Diano, Ivaldo da Silva, Balazs Horvath & Tamas L Horvath

  2. Geriatric Research Education and Clinical Center (GRECC), VA Medical Center, St. Louis, 63106, Missouri, USA

    Susan A Farr, F Spencer Gaskin, Naoko Nonaka, Laura B Jaeger, William A Banks & John E Morley

  3. Department of Internal Medicine, Division of Geriatric Medicine, St. Louis University School of Medicine, St. Louis, 63106, Missouri, USA

    Susan A Farr, F Spencer Gaskin, Naoko Nonaka, Laura B Jaeger, William A Banks & John E Morley

  4. Department of Psychiatry, University of Cincinnati, Cincinnati, 45237, Ohio, USA

    Stephen C Benoit & Matthias H Tschöp

  5. Department of Internal Medicine, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Ewan C McNay & Robert S Sherwin

  6. Department of Molecular Genetics, Howard Hughes Medical Institute, Rockefeller University, New York, 10021, New York, USA

    Shirly Pinto

  7. Department of Neurology, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Lin Xu & Kelvin A Yamada

  8. Regeneron Pharmaceuticals Inc., Tarrytown, 10591, New York, USA

    Mark W Sleeman

  9. Department of Neurobiology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Sabrina Diano & Tamas L Horvath

  10. Section of Comparative Medicine, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Tamas L Horvath

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Correspondence to Tamas L Horvath.

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Supplementary information

Supplementary Figure 1

Illustration of unbiased spine synapse quantification on electron micrographs. (PDF 484 kb)

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Diano, S., Farr, S., Benoit, S. et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci 9, 381–388 (2006). https://doi.org/10.1038/nn1656

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