title: Local infusion of ghrelin enhanced hippocampal synaptic plasticity and spatial memory through activation of phosphoinositide 3-kinase in the dentate gyrus of adult rats.
abstract: Ghrelin, an orexigenic hormone, is mainly produced by the stomach and released into the circulation. Ghrelin receptors (growth hormone secretagogue receptors) are expressed throughout the brain, including the hippocampus. The activation of ghrelin receptors facilitates high-frequency stimulation (HFS)-induced long-term potentiation (LTP) in vitro, and also improves learning and memory. Herein, we report that a single infusion of ghrelin into the hippocampus led to long-lasting potentiation of excitatory postsynaptic potentials (EPSPs) and population spikes (PSs) in the dentate gyrus of anesthetized rats. This potentiation was accompanied by a reduction in paired-pulse depression of the EPSP slope, an increase in paired-pulse facilitation of the PS amplitude, and an enhancement of EPSP-spike coupling, suggesting the involvement of both presynaptic and postsynaptic mechanisms. Meanwhile, ghrelin infusion time-dependently increased the phosphorylation of Akt-Ser473, a downstream molecule of phosphoinositide 3-kinase (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 extracellular signal-regulated kinase (ERK)1/2. The Morris water maze test showed that ghrelin enhanced spatial memory, and that this was prevented by pretreatment with PI3K inhibitor. Taken together, the findings show that: (i) a single infusion of ghrelin induced a new form of synaptic plasticity by activating the PI3K signaling pathway, without HFS and NMDA receptor activation; (ii) a single infusion of ghrelin also enhanced the maintenance of HFS-induced LTP through ERK activation; and (iii) repetitive infusion of ghrelin enhanced spatial memory by activating the PI3K signaling pathway. Thus, we propose that the ghrelin signaling pathway could have therapeutic value in cognitive deficits.
authors.affiliation: School of Life Science, University of Science and Technology of China, Hefei, Anhui, China The Neurobiology Institute of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Tairan
authors.initials: T
authors.lastname: Xing
authors.forename: Ming
authors.initials: M
authors.lastname: Wang
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Miao
authors.forename: Mingliang
authors.initials: M
authors.lastname: Tang
authors.forename: Jutao
authors.initials: J
authors.lastname: Chen
authors.forename: Guangwu
authors.initials: G
authors.lastname: Li
authors.forename: Di-Yun
authors.initials: DY
authors.lastname: Ruan
mesh_terms: D000818:Animals; D018891:Dentate Gyrus / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology*; D004789:Enzyme Activation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D054439:Ghrelin / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D054439:Ghrelin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate