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Glucagon-like peptide-1 receptor is involved in learning and neuroprotection

Nature Medicine volume 9, pages 1173–1179 (2003)Cite this article

Abstract

Glucagon-like peptide-1 (GLP-1) is a gut peptide that, together with its receptor, GLP-1R, is expressed in the brain. Here we show that intracerebroventricular (i.c.v.) GLP-1 and [Ser(2)]exendin(1–9) (HSEGTFTSD; homologous to a conserved domain in the glucagon/GLP-1 family) enhance associative and spatial learning through GLP-1R. [Ser(2)]exendin(1–9), but not GLP-1, is also active when administered peripherally. GLP-1R-deficient mice have a phenotype characterized by a learning deficit that is restored after hippocampal Glp1r gene transfer. In addition, rats overexpressing GLP-1R in the hippocampus show improved learning and memory. GLP-1R-deficient mice also have enhanced seizure severity and neuronal injury after kainate administration, with an intermediate phenotype in heterozygotes and phenotypic correction after Glp1r gene transfer in hippocampal somatic cells. Systemic administration of [Ser(2)]exendin(1–9) in wild-type animals prevents kainate-induced apoptosis of hippocampal neurons. Brain GLP-1R represents a promising new target for both cognitive-enhancing and neuroprotective agents.

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Figure 1: Effects of i.c.v. GLP-1 and [Ser(2)]exendin(1–9) on associative and spatial learning.
Figure 2: Enhancement of learning and memory by intranasal [Ser(2)]exendin(1–9).
Figure 3: Behavioral phenotype of wild-type Glp1r+/+, heterozygous Glp1r+/− and homozygous Glp1r−/− knockout mice, and rescue of Glp1r−/− phenotype by recombinant AAV–mediated intrahippocampal gene transfer of Glp1r.
Figure 4: Overexpression of GLP-1R in rat hippocampus with recombinant AAV.
Figure 5: Kainic acid neurotoxicity in Glp1r knockout mice and effects of intranasal [Ser(2)]exendin(1–9) in rats.
Figure 6: Effects of [Ser(2)]exendin(1–9) on MAP kinase pathway.

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Acknowledgements

We thank A. Brooks, L. Cunningham, R. Horst and C. Leichtlein for scientific and technical input and helpful discussions. This work was supported in part by the Jefferson Faculty Foundation, National Institutes of Health, European Molecular Biology Organization, New Zealand Health Research Council, New Economy Research Fund and Marsden Fund of New Zealand.

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Authors and Affiliations

  1. Department of Molecular Medicine and Pathology, University of Auckland, Private Bag 92019, Auckland, 86716, New Zealand

    Matthew J During, Jeremy S Francis, Helen L Fitzsimons & Matthias Klugmann

  2. Department of Neurosurgery, CNS Gene Therapy Center, Jefferson Medical College, 1025 Walnut Street, Philadelphia, 19107, Pennsylvania, USA

    Matthew J During, Lei Cao, David S Zuzga, Helen L Fitzsimons, Xiangyang Jiao, Ross J Bland & Colin N Haile

  3. Veterans Affairs Medical Center-St. Louis and Division of Geriatrics, Department of Internal Medicine, GRECC, Saint Louis University School of Medicine, St. Louis, 63106, Missouri, USA

    William A Banks

  4. Department of Medicine, Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, 200 Elizabeth Street CCRW3-838, Toronto, M5G 2C4, Ontario, Canada

    Daniel J Drucker

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Correspondence to Matthew J During.

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M.J.D. and C.N.H. are coauthors on a patent application related to [Ser(2)]exendin(1–9), which is assigned to Thomas Jefferson University.

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During, M., Cao, L., Zuzga, D. et al. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med 9, 1173–1179 (2003). https://doi.org/10.1038/nm919

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