The Effect And Mechanism Of Ghrelin On Hippocampal Learning And Memory

Ghrelin, an orexigenic hormone, is mainly produced by stomach and released to circulation. Ghrelin receptors (GHS-R) are expressed throughout the brain, including hippocampus. The activation of GHS-R facilitates high-frequency stimulation (HFS)-induced long term potentiation (LTP) in vitro, and also improves learning and memory.In this paper, we investigated the effect and mechanism of ghrelin on hippocampal learning and memory. The results showed that: (1) Single infusion of ghrelin in hippocampus led to long-lasting potentiation of excitatory postsynaptic potential (EPSP) and population spike (PS) in the dentate gyrus (DG) of anesthetized rats. This potentiation was accompanied with a reduction of paired-pulse depression (PPD) of EPSP slope, an increase of paired-pulse facilitation (PPF) of PS amplitude and an enhancement of EPSP-spike coupling, suggesting the involvement of both pre- and post-synaptic mechanisms. (2) Ghrelin infusion time-dependently increased the phosphorylation of Akt-Ser473, a downstream molecule of PI3K. Interestingly, PI3K inhibitors, but not NMDA receptor antagonist, inhibited ghrelin-induced potentiation. Although ghrelin had no effect on the induction of HFS-induced LTP, it prolonged the expression of HFS-induced LTP through ERK1/2 signal molecular. (3) Morris water maze test showed that ghrelin enhanced spatial memory, which was prevented by pretreatment with PI3K inhibitor. Taken together, 1) a single infusion of ghrelin could induce a new form of synaptic plasticity through activating PI3K signal pathway, without HFS and NMDA receptor activation; 2) a single infusion of ghrelin could also enhance the maintenance of HFS-induced LTP through ERK activation; 3) repetitive infusion of ghrelin could enhance spatial memory through activating PI3K signal pathway.Thus, we propose that ghrelin signaling pathway could have therapeutic values for cognitive deficits.