Although ghrelin and its cognate receptor GHSR1a are highly localized in the hypothalamic nuclei for the regulation of metabolic states and feeding, GHSR1a is also highly localized in the hippocampus suggesting its involvement in extra-hypothalamic functions. Indeed, exogenous application of ghrelin is reported to improve hippocampal learning and memory. However, the underlying mechanism of ghrelin regulation of hippocampal functions is poorly understood. Here we report ghrelin promoted phosphorylation of GluN1 and amplified NMDA receptor (NMDAR)-mediated EPSCs in the CA1 pyramidal cell of hippocampus in slice preparations. The ghrelin-induced responses were sensitive to a GHSR1a antagonist and inverse agonist, and were absent in GHSR1a homozygous (-/-) knock-out mice. These results indicated that activation of GHSR1a was critical in the ghrelin-induced enhancement of the NMDAR function. Interestingly, heterozygous (+/-) mouse hippocampi were also insensitive to ghrelin treatment, suggesting a slight reduction in the availability of GHSR1a may be sufficient to negate the effect of ghrelin on GluN1 phosphorylation and NMDAR channel activities. In addition, NMDAR-mediated spike current, which is of dendritic origin, was blocked by the GHSR1a antagonist, suggesting the presence of GHSR1a on the pyramidal cell dendrites with physical proximity to NMDAR. Together with our findings on the localization of GHSR1a in the CA1 region of the hippocampus, which was evidenced by fluorescent ghrelin binding, immunoreactivity, and eGFP reporter gene expression, we conclude that the activation of GHSR1a favors a rapid modulation of the NMDA receptor-mediated glutamatergic synaptic transmission by phosphorylating GluN1 subunit in the hippocampus.
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