Nature Medicine
9, 1173 - 1179 (2003)
Published online: 17 August 2003; | doi:10.1038/nm919
Glucagon-like peptide-1 receptor is involved in learning and neuroprotectionMatthew J During1, 2, Lei Cao2, David S Zuzga2, Jeremy S Francis1, Helen L Fitzsimons1, 2, Xiangyang Jiao2, Ross J Bland2, Matthias Klugmann1, William A Banks3, Daniel J Drucker4
& Colin N Haile21
Department of Molecular Medicine and Pathology, University of Auckland, Private Bag 92019, Auckland 86716, New Zealand. 2
CNS Gene Therapy Center, Department of Neurosurgery, Jefferson Medical College, 1025 Walnut Street, Philadelphia, Pennsylvania 19107, USA. 3
GRECC, Veterans Affairs Medical Center-St. Louis and Division of Geriatrics, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri 63106, USA. 4
Department of Medicine, Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, 200 Elizabeth Street CCRW3-838, Toronto, Ontario M5G 2C4, Canada.
Correspondence should be addressed to Matthew J During m.during@auckland.ac.nzGlucagon-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.
|
cells through GPR40
