Receptors for the incretin glucagon-like peptide-1 are expressed on neurons in the central nervous system

Abstract

Glucagon-like-peptide-1 is an incretin hormone that also has neuroprotective properties. Here we analyse where glucagon-like-peptide-1 receptors are expressed in the brain. The receptor is found only on neurons, not on glia cells. The pyramidal cell layer of the CA region and the granule cell layer of the dentate gyrus in the hippocampus show intense staining. In the neocortex, larger pyramidal neurons express the receptor. In the cerebellum, only Purkinje neurons express the receptor. Dendrites of larger neurons were stained; in particular, pyramidal cells in area CA and dendrites of Purkinje cells. The fact that the receptor is located on neurons and dendrites suggests that the neuroprotective action is caused by the modulation of neuronal excitation.

Modulation of Glucagon-like Peptide-1 (GLP-1) Potency by Endocannabinoid-like Lipids Represents a Novel Mode of Regulating GLP-1 Receptor Signaling

“…GLP1Rs in the brain stem are considered activated by the centrally derived GLP-1, which is transmitted through neural fibers in most of brain areas (11,12,40). However, neurons expressing GLP-1Rs in notable areas, such as caudal hippocampus and the dopaminergic neurons in the substantia nigra, have no apparent innervations from GLP-1-producing neurons (1,3,14). Both areas are anatomic sites of deficient functions in disease that are ameliorable by GLP-1 analog therapy, which improves memory/learning in an Alzheimer mouse model and Parkinson symptoms in humans (5,6,41).…”

“…These neurons send abundant projections to other regions of the brain, including the forebrain, hypothalamus, amygdala, stria terminalis, and thalamus, where GLP-1Rs are expressed; this neuronal circuit of GLP-1 signaling is considered relevant to satiety and energy homeostasis (2,11). GLP-1R is also expressed in neurons in the hippocampus (1) and dopaminergic neurons in substantia nigra (3), where no known GLP-1-secreting neuron innervation is found (3,14). It has been suggested that the basal circulating GLP-1 level is the primary source of ligands accessible to GLP-1Rs in these brain regions and probably in the heart as well.…”

“…human pancreatic islet ␤ cells, GLP-1R is expressed in a wide array of tissues, including lung, heart, kidney, blood vessels, neurons, and lymphocytes (1)(2)(3)(4). Mice deficient in GLP-1R expression or with blunted GLP-1R function show impairment of physiologic features not limited to glucose homeostasis but also including learning and memory (4).…”

Actions of exendin-4 therapy on cognitive function and hippocampal synaptic plasticity in mice fed a high-fat diet

“…1 Interestingly, GLP-1 receptors are expressed within the neocortex and hippocampal regions of the brain, which are key areas responsible for modulating learning and memory processes. 2 Indeed, mice with targeted deletion of the GLP-1 receptor exhibit demonstrable impairments in synaptic plasticity and cognitive performance whereas over-expression of GLP-1 in the hippocampus enhanced spatial learning. 3,4 In addition, GLP-1 has neuroprotective properties, protecting neurons from kainite-induced neurotoxicity and reducing hippocampal neuronal apoptosis.…”

GLP-1 and Exendin-4 Transiently Enhance GABAA Receptor–Mediated Synaptic and Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons

“…The best known effects of GLP-1 are to stimulate insulin and inhibit glucagon secretion in a glucose-dependent manner in the pancreatic islets to regulate glucose homeostasis after a meal (13). Although the GLP-1 receptor is expressed in the hippocampus (10, 16,17) and GLP-1 and its mimetics, e.g., exendin-4, liraglutide, might potentially be used to treat cognitive declines related to diabetes (6,7), to date not much is known about the effects of GLP-1 on neuronal signaling and, hence, how GLP-1 affects cognition and hippocampal regulation of metabolic homeostasis.…”