Activation of GHSRs Facilitates the Excitability of Dentate Gyrus Granule Cells and Short-Term Spatial Memory via Multiple Ionic and Signaling Mechanisms

Abstract

Ghrelin is the endogenous ligand of the ghrelin secretagogue receptors (GHSRs). Although the GHSRs are densely expressed in the dentate gyrus (DG) granule cells (GCs), their roles in the DG GCs remain to be fully understood. We probed the actions of ghrelin on the DG GCs with whole-cell recordings and its effects on short-term spatial memory using the Y-maze spontaneous alternation test. Application of ghrelin excited the DG GCs by depressing the G protein-coupled inwardly rectifying K⁺ (GIRK) channels and ATP-sensitive K⁺ (K_ATP) channels, activating the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and a TTX-resistant, persistent Na⁺ channel. Adenylyl cyclase and EPAC2 were required, whereas phospholipase C and protein kinase A were not needed for the ghrelin-mediated excitation of DG GCs. Overnight fasting augmented the excitability of the DG GCs via activation of GHSRs, suggesting a role for endogenously released ghrelin. Ghrelin also enhanced synaptic recruitment of action potentials in DG GCs. Microinjection of ghrelin into the DG increased the alternating sequences in the Y maze test via GHSR-mediated elevation of cAMP and EPAC signals. Our results provide an action mode to explain the roles of GHSRs in improving cognitive functions.