Ghrelin Increases Glutamate Release at the Perforant Path‐Dentate Gyrus Granule Cell Synapses by Cross‐Activating Dopamine D ₁ Receptors

Ghrelin is a multifunctional peptide hormone with receptors present in various brain tissues including the hippocampus and has been associated with neuroprotection, neuromodulation, and memory processing. Ghrelin is an endogenous ligand for growth hormone secretagogue receptors (GHSRs). Here we studied the roles and mechanisms of ghrelin in glutamatergic transmission at the perforant path (PP)-granule cell (GC) synapses in the dentate gyrus by recording AMPA EPSCs in hippocampal slices cut from both male and female C57BL/6 J mice. Our results showed that ghrelin concentration-dependently elicited a persistent enhancement of AMPA EPSCs. The ghrelin-induced augmentation of glutamatergic transmission was mediated by increasing presynaptic glutamate release because ghrelin decreased the coefficient of variation (C.V.) and paired-pulse ratio of AMPA EPSCs, increased NMDA EPSCs as well and enhanced the frequency with no effect on the amplitude of mEPSCs. Ghrelin enlarged the size of readily releasable pool and increased release probability. Ghrelin-elicited increases in glutamate release did not require the functions of Gαq-phospholipase C pathway and Gαi, but was dependent on Gαs and cAMP/EPAC/PI3K pathway. As GHSRs have been shown to activate cAMP signals via heterodimerization with dopamine D₁ receptors, we probed the roles of D₁ receptors in ghrelin-mediated facilitation of glutamate release. Our results indicated that ghrelin enhanced glutamate release via interaction with D₁ receptors. Our results may provide a novel cellular and molecular mechanism whereby ghrelin enhances glutamatergic transmission.