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

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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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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