Ghrelin accelerates synapse formation and activity development in cultured cortical networks

Abstract

BackgroundWhile ghrelin was initially related to appetite stimulation and growth hormone secretion, it also has a neuroprotective effect in neurodegenerative diseases and regulates cognitive function. The cellular basis of those processes is related to synaptic efficacy and plasticity. Previous studies have shown that ghrelin not only stimulates synapse formation in cultured cortical neurons and hippocampal slices, but also alters some of the electrophysiological properties of neurons in the hypothalamus, amygdala and other subcortical areas. However, direct evidence for ghrelin’s ability to modulate the activity in cortical neurons is not available yet. In this study, we investigated the effect of acylated ghrelin on the development of the activity level and activity patterns in cortical neurons, in relation to its effect on synaptogenesis. Additionally, we quantitatively evaluated the expression of the receptor for acylated ghrelin – growth hormone secretagogue receptor-1a (GHSR-1a) during development.ResultsWe performed electrophysiology and immunohistochemistry on dissociated cortical cultures from neonates, treated chronically with acylated ghrelin. On average 76 ± 4.6% of the cortical neurons expressed GHSR-1a. Synapse density was found to be much higher in ghrelin treated cultures than in controls across all age groups (1, 2 or 3 weeks). In all cultures (control and ghrelin treated), network activity gradually increased until it reached a maximum after approximately 3 weeks, followed by a slight decrease towards a plateau. During early developmental stages (1–2 weeks), the activity was much higher in ghrelin treated cultures and consequently, they reached the plateau value almost a week earlier than controls.ConclusionsAcylated ghrelin leads to earlier network formation and activation in cultured cortical neuronal networks, the latter being a possibly consequence of accelerated synaptogenesis.

Acyl Ghrelin Improves Synapse Recovery in an In Vitro Model of Postanoxic Encephalopathy

“…Previously, we reported that AG accelerates synaptogenesis and synaptic activity under healthy conditions [23, 24]. Supposed working mechanisms for stimulating synapse growth or recovery include activation of several signaling pathways.…”

“…Three hours after restoration of normoxia, half of the remaining cultures were supplemented with ghrelin (Abcam, Cambridge, UK) for 24 h, at a final concentration of 1 μM, as described elsewhere [24, 26, 27, 36, 37]. The other half of the cultures were kept in a plain medium, also for 24 h, and used as control.…”

“…Previously, we have shown improvements of network connectivity along with an increased number of synapses, resulting from chronic stimulation of dissociated cortical neurons with ghrelin [23, 24]. Ghrelin is multifunctional 28-aminoacid hormone and a neuropeptide originally not only found in the rat stomach [25], but also identified in the hypothalamus, to a lesser extent in the hippocampus and brain cortex [26–28], as well as in the adipose tissue [29].…”

Clarifying the Ghrelin System’s Ability to Regulate Feeding Behaviours Despite Enigmatic Spatial Separation of the GHSR and Its Endogenous Ligand

“…To begin, many independent groups have detected ghrelin mRNA within the brain (most commonly within the HYP) [20,22,24,56,214,215,216,217,218,219]. Second, the hypothalamic expression of ghrelin and GOAT mRNA fluctuate with feeding status (i.e., upregulated following a 48 h fast in rats) [56].…”

Involvement of Astrocytes in Mediating the Central Effects of Ghrelin

“…Other actions of this gut hormone that have been less studied include modulation of reward systems [28] together with learning and memory performance [10]. It also plays a protective role against neurodegenerative diseases [29,30,31]. Thus, ghrelin emerges as a hormone with a wide range of functions and possible therapeutic applications, although much is yet to be learned concerning its mechanisms of action.…”