Ghrelin increases memory consolidation through hippocampal mechanisms dependent on glutamate release and NR2B-subunits of the NMDA receptor
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Ghrelin (Ghr) is a peptide that participates in the modulation of several biological processes. Ghr administration into the hippocampus improves learning and memory in different memory tests. However, the possible mechanisms underlying this effect on memory have not yet been clarified.
The purpose of the present work is to add new insights about the mechanisms by which Ghr modulates long-term memory consolidation in the hippocampus. We examined Ghr effects upon processes related to increased synaptic efficacy as presynaptic glutamate release and changes in the expression of the NR2B-subunits containing n-methyl-d-aspartate receptors (NMDAR), which are critical for LTP induction. We also attempted to determine the temporal window in which Ghr administration induces memory facilitation and if the described effects depend on GHS-R1a stimulation.
The present research demonstrated that Ghr increased glutamate release from hippocampal synaptosomes; intra-hippocampal Ghr administration increased NR2B-subunits expression in CA1 and DG subareas and also reversed the deleterious effects of the NR2B-subunit-specific antagonist, Ro 25-6981, upon memory consolidation and LTP generation in the hippocampus. These effects are likely to be the consequence of GHS-R1a activation.
According to the results above mentioned and previous findings, we can hypothesize some of the mechanisms by which Ghr modulates memory consolidation. At presynaptic level, Ghr stimulates glutamate release, probably by enhancing [Ca2+]i. At postsynaptic level, the glutamate released activates NMDAR while Ghr also mediates effects directly activating its specific receptors and increases NR2B-subunit expression.
KeywordsGhrelin Memory consolidation Glutamate release LTP NR2B subunit
- Bednarek MA, Feighner SD, Pong SS, McKee KK, Hreniuk DL, Silva MV, Warren VA, Howard AD, Van Der Ploeg LH, Heck JV (2000) Structure-function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a. J Med Chem 43(23):4370–4376CrossRefPubMedGoogle Scholar
- Brenman JE, Chao DS, Gee SH, McGee AW, Craven SE, Santillano DR, Wu Z, Huang F, Xia H, Peters MF, Froehner SC, Bredt DS (1996) Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and alpha1-syntrophin mediated by PDZ domains. Cell 84(5):757–767CrossRefPubMedGoogle Scholar
- Carlini VP, Varas MM, Cragnolini AB, Schiöth HB, Scimonelli TN, de Barioglio SR (2004) Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin. Biochem Biophys Res Commun 313(3):635–641CrossRefPubMedGoogle Scholar
- Flores-Barrera E, Thomases DR, Heng LJ, Cass DK, Caballero A, Tseng KY (2014) Late adolescent expression of GluN2B transmission in the prefrontal cortex is input-specific and requires postsynaptic protein kinase A and D1 dopamine receptor signaling. Biol Psychiatry 75(6):508–516CrossRefPubMedCentralPubMedGoogle Scholar
- Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS, Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rigby M, Sirinathsinghji DJ, Dean DC, Melillo DG, Patchett AA, Nargund R, Griffin PR, DeMartino JA, Gupta SK, Schaeffer JM, Smith RG, Van der Ploeg LH (1996) A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273:974–977CrossRefPubMedGoogle Scholar
- Kohno D, Gao HZ, Muroya S, Kikuyama S, Yada T (2003) Ghrelin directly interacts with neuropeptide-Y-containing neurons in the rat arcuate nucleus: Ca2+ signaling via protein kinase A and N-type channel-dependent mechanisms and cross-talk with leptin and orexin. Diabetes 52(4):948–956CrossRefPubMedGoogle Scholar
- Murphy JA, Stein IS, Lau CG, Peixoto RT, Aman TK, Kaneko N, Aromolaran K, Saulnier JL, Popescu GK, Sabatini BL, Hell JW, Zukin RS (2014) Phosphorylation of Ser1166 on GluN2B by PKA is critical to synaptic NMDA receptor function and Ca2+ signaling in spines. J Neurosci 34(3):869–879CrossRefPubMedCentralPubMedGoogle Scholar
- Paxinos G, Watson C (2009) The rat brain in stereotaxic coordinates, compact, 6th edn. Academic, San DiegoGoogle Scholar
- Sprengel R, Suchanek B, Amico C, Brusa R, Burnashev N, Rozov A, Hvalby O, Jensen V, Paulsen O, Andersen P, Kim JJ, Thompson RF, Sun W, Webster LC, Grant SG, Eilers J, Konnerth A, Li J, McNamara JO, Seeburg PH (1998) Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo. Cell 92:279–289CrossRefPubMedGoogle Scholar
- von Engelhardt J, Doganci B, Jensen V, Hvalby Ø, Göngrich C, Taylor A, Barkus C, Sanderson DJ, Rawlins JN, Seeburg PH, Bannerman DM, Monyer H (2008) Contribution of hippocampal and extra-hippocampal NR2B-containing NMDA receptors to performance on spatial learning tasks. Neuron 60:846–860CrossRefGoogle Scholar