Ghrelin controls hippocampal spine synapse density and memory performance

Abstract

The gut hormone and neuropeptide ghrelin affects energy balance and growth hormone release through hypothalamic action that involves synaptic plasticity in the melanocortin system. Ghrelin binding is also present in other brain areas, including the telencephalon, where its function remains elusive. Here we report that circulating ghrelin enters the hippocampus and binds to neurons of the hippocampal formation, where it promotes dendritic spine synapse formation and generation of long-term potentiation. These ghrelin-induced synaptic changes are paralleled by enhanced spatial learning and memory. Targeted disruption of the gene that encodes ghrelin resulted in decreased numbers of spine synapses in the CA1 region and impaired performance of mice in behavioral memory testing, both of which were rapidly reversed by ghrelin administration. Our observations reveal an endogenous function of ghrelin that links metabolic control with higher brain functions and suggest novel therapeutic strategies to enhance learning and memory processes.

Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

“…The ghrelin mimetic capromorelin and the presumed GHSR antagonist A778193 (found in this study to be a GHSR inverse agonist) were generously provided by Dr. Luc Ver Donck and Dr. Dieder Moechars. The ghrelin fragments (1-5) amide, (1-7), (1-9), (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11), (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), and (23-28) were supplied by Phoenix Pharmaceuticals (Karlsruhe, Germany). All other chemicals were analytical reagent grade or better and were supplied by Merck (Darmstadt, Germany).…”

“…Individual sampling times were set at 20 minutes each. Each experiment started with the collection of intrahippocampal basal samples (1)(2)(3)(4)(5)(6) in which the perfusion fluid was composed of only modified Ringer's solution. Consecutively, ghrelin, capromorelin, A778193, [D-Arg 1 ,D-Phe 5 , D-Trp 7,9 ,Leu 11 ]substance P, or ghrelin (1-5) amide were dissolved in modified Ringer's solution and perfused through the hippocampal microdialysis probe from the 7th collection period onward.…”

“…Cells were subcultured at 70 to 80 % confluency and re-suspended in 96-well plates at 60,000 cells per well. Concentrations of A778193 were added in quadruplicate to the cells and incubated for 90 minutes at 37°C in air/CO 2 (1-7), (1-9), (1-11), (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), and (23)(24)(25)(26)(27)(28) were tested next to the GHSR agonist capromorelin. A sigmoidal dose response curve was fitted using GraphPad Prism software, GraphPad Software, (La Jolla, USA), yielding a pEC 50 and curve maximum.…”

“…This 28 amino-acid bioactive peptide displays several important biological effects, including an influence on pituitary hormone secretion, appetite, metabolism, gastrointestinal function, and memory [2][3][4]. Ghrelin is best known as the endogenous ligand of the growth hormone secretagogue receptor (GHSR).…”

“…Being a gutderived hormone, the major emphasis of ghrelin research has been directed toward its orexigenic action via neuropeptide Y/agouti-related protein activation in the hypothalamus [3]. As for the hippocampus, peripheral ghrelin was shown to enter this brain region to bind to the GHSR, where it promoted spine synapse formation in the stratum radiatum of the CA1 subfield as well as facilitated long-term potentiation generation, which were paralleled by enhanced spatial learning and memory [2]. Since then, various reports have implicated ghrelin in hippocampal functions, and more recently in epilepsy mechanisms [7][8][9][10][11].…”