Glucagon‐like peptide‐1 cleavage product GLP‐1 (9‐36) amide enhances hippocampal long‐term synaptic plasticity in correlation with suppression of Kv4.2 expression and eEF2 phosphorylation

Glucagon‐like peptide‐1 (GLP‐1) is an endogenous gut hormone and a key regulator in maintaining glucose homeostasis by stimulating insulin secretion. Its natural cleavage product GLP‐1 (9‐36), used to be considered a “bio‐inactive” metabolite mainly because of its lack of insulinotropic effects and low affinity for GLP‐1 receptors, possesses unique properties such as anti‐oxidant and cardiovascular protection. Little is known about the role of GLP‐1 (9‐36) in central nervous system. Here we report that chronic, systemic application of GLP‐1 (9‐36) in adult mice facilitated both the induction and maintenance phases of hippocampal long‐term potentiation (LTP), a major form of synaptic plasticity. In contrast, spatial learning and memory, as assessed by the Morris water maze test, was not altered by GLP‐1 (9‐36) administration. At the molecular level, GLP‐1 (9‐36) reduced protein levels of the potassium channel Kv4.2 in hippocampus, which is linked to elevated dendritic membrane excitability. Moreover, GLP‐1(9‐36) treatment inhibited phosphorylation of mRNA translational factor eEF2, which is associated with increased capacity for de novo protein synthesis. Finally, we showed that the LTP‐enhancing effects by GLP‐1 (9‐36) treatment in vivo were blunted by application of exendin(9‐39)amide [EX(9‐39)], the GLP‐1 receptor (GLP‐1R) antagonist, suggesting its role as a GLP‐1R agonist. These findings demonstrate that GLP‐1 (9‐36), which was considered a “bio‐inactive” peptide, clearly exerts physiological effects on neuronal plasticity in the hippocampus, a brain region critical for learning and memory.