Ghrelin increases memory consolidation through hippocampal mechanisms dependent on glutamate release and NR2B-subunits of the NMDA receptor.

MARISA GHERSI,; LAURA GABACH; BUTTELER FLORENCIA; VILCAES A; SCHIÖTH HB; MARIELA F. PÉREZ; DE BARIOGLIO SR

PSYCHOPHARMACOLOGY

SPRINGER

Lugar: Berlin; Año: 2014 vol. 232 p. 1843 - 1857

0033-3158

Ghrelin (Ghr) is a 28 amino acid peptide that participates in the modulation of several processes related to energy homeostasis, gastrointestinal functions, anxiety-like behavior and growth hormone releasing activity. It has been shown that in-vivo, the administration of Ghr into the hippocampus (hp) improves learning and memory in different behavioral paradigms such as the step down and object recognition tests. However, the possible mechanisms underlying this effect on memory facilitation have not yet been clarified. In this work, we combined electrophysiology, evoked glutamate release from synaptosomes, behavioral paradigms, immunohistochemical detection, pharmacological NMDAR blockade and hippocampal neurons cultures in order to examine if the increase in synaptic efficacy induced by Ghr in hp could be related to A) changes in glutamate release from synaptosomes, B) modification in [Ca2+]i levels in hippocampal neurons C) changes in the expression of the NR2B-subunits containing NMDAR. We also studied if Ghr could to revert the cognitive deficit and LTP impairment induced by an NR2B-specific antagonist, Ro-26181. The results provided the first evidence that Ghr increases glutamate release from hippocampal synaptosomes and it also increases the fluorescence in hippocampal neurons indicating the corresponding augment of [Ca2+]i levels. In addition, we also demonstrated that the intra-hippocampal administration of Ghr enhances NR2B-subunits expression in the CA1 and DG areas of the hp. In addition, Ghr also reversed the deleterious effects of the NR2B-specific antagonist, Ro-26181, upon behavioral and electrophysiological parameters in this structure. These effects are consequence of the specific stimulation of GHS-R1a, since administration of selective antagonist D-Lys3-GHRP-6, prior to the peptide, prevented the Ghr-induced behavioral and electrophysiological effects.