Exendin-4 increases the firing activity of hippocampal CA1 neurons through TRPC4/5 channels

The central neuropeptide GLP-1 is synthesized by preproglucagon (PPG) neurons in the brain. GLP-1 receptors are widely distributed in central nervous system. Hippocampus is a key component of the limbic system which is involved in learning, memory, and cognition. Previous studies have shown that overexpression of GLP-1 receptors in the hippocampus could improve the process of learning and memory. However, up to now, the direct electrophysiological effects and possible molecular mechanisms of GLP-1 in hippocampal CAl neurons remain unexplored. The present study aims to evaluate the effects and mechanisms of GLP-1 on the spontaneous firing activity of hippocampal CAl neurons. Employing multibarrel single-unit extracellular recordings, the present study showed that micro-pressure administration of GLP-1 receptor agonist, exendin-4, significantly increased the spontaneous firing rate of hippocampal CA1 neurons in rats. Furthermore, application of the specific GLP-1 receptor antagonist, exendin(9−39), alone significantly decreased the firing rate of CA1 neurons, suggesting that endogenous GLP-1 modulates the firing activity of CA1 neurons. Co-application of exendin(9−39) completely blocked exendin-4-induced excitation of hippocampal CA1 neurons. Finally, the present study demonstrated for the first time that the transient receptor potential canonical 4 (TRPC4)/TRPC5 channels may be involved in exendin-4-induced excitation. The present studies may provide a rationale for further investigation of the modulation of GLP-1 on learning and memory as well as its possible involvement in Alzheimer's disease.