Glucagon-like peptide-1 receptor is involved in learning and neuroprotection.
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.
During
Matthew J
MJ
Department of Molecular Medicine and Pathology, University of Auckland, Private Bag 92019, Auckland 86716, New Zealand. m.during@auckland.ac.nz
Cao
Lei
L
Zuzga
David S
DS
Francis
Jeremy S
JS
Fitzsimons
Helen L
HL
Jiao
Xiangyang
X
Bland
Ross J
RJ
Klugmann
Matthias
M
Banks
William A
WA
Drucker
Daniel J
DJ
Haile
Colin N
CN
D000281:Administration, Intranasal; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D003071:Cognition / Q000187:drug effects; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005934:Glucagon / Q000008:administration & dosage / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007608:Kainic Acid / Q000009:adverse effects; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D011498:Protein Precursors / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011498:Protein Precursors; D018027:Receptors, Glucagon; C478740:exendin (1-9), Ser(2)-; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D007608:Kainic Acid