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

Matthew J. During, Lei Cao, David S. Zuzga, Jeremy S. Francis, Helen L. Fitzsimons, Xiangyang Jiao, Ross J. Bland, Matthias Klugmann, William A. Banks, Daniel J. Drucker, Colin N. Haile

Research output: Contribution to journalArticlepeer-review

582 Scopus citations

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 Gilp1r 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.

Original languageEnglish (US)
Pages (from-to)1173-1179
Number of pages7
JournalNature Medicine
Volume9
Issue number9
DOIs
StatePublished - Sep 1 2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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