Synaptic enhancement induced by gintonin via lysophosphatidic acid receptor activation in central synapses

Abstract

Park H, Kim S, Rhee J, Kim HJ, Han JS, Nah SY, Chung C. Synaptic enhancement induced by gintonin via lysophosphatidic acid receptor activation in central synapses. J Neurophysiol 113: 1493-1500, 2015. First published December 10, 2014 doi:10.1152/jn.00667.2014 is one of the well-characterized, ubiquitous phospholipid molecules. LPA exerts its effect by activating G protein-coupled receptors known as LPA receptors (LPARs). So far, LPAR signaling has been critically implicated during early development stages, including the regulation of synapse formation and the morphology of cortical and hippocampal neurons. In adult brains, LPARs seem to participate in cognitive as well as emotional learning and memory. Recent studies using LPAR1-deficient mice reported impaired performances in a number of behavioral tasks, including the hippocampus-dependent spatial memory and fear conditioning tests. Nevertheless, the effect of LPAR activation in the synaptic transmission of central synapses after the completion of embryonic development has not been investigated. In this study, we took advantage of a novel extracellular agonist for LPARs called gintonin to activate LPARs in adult brain systems. Gintonin, a recently identified active ingredient in ginseng, has been shown to activate LPARs and mobilize Ca 2ϩ in an artificial cell system. We found that the activation of LPARs by application of gintonin acutely enhanced both excitatory and inhibitory transmission in central synapses, albeit through tentatively distinct mechanisms. Gintonin-mediated LPAR activation primarily resulted in synaptic enhancement and an increase in neuronal excitability in a phospholipase C-dependent manner. Our findings suggest that LPARs are able to directly potentiate synaptic transmission in central synapses when stimulated exogenously. Therefore, LPARs could serve as a useful target to modulate synaptic activity under pathological conditions, including neurodegenerative diseases. synaptic potentiation; lysophosphatidic acid receptor; ginseng; gintonin LYSOPHOSPHATIDIC ACID (LPA) is one of the well-characterized, ubiquitous phospholipids and exerts its effect by activating G protein-coupled receptors known as LPA receptors 1-5 (LPAR1-LPAR5; Choi et al. 2010). A number of studies have shown that LPAR signaling plays a critical role during early development stages, including the regulation of synapse formation and the morphology of cortical and hippocampal neurons (Dubin et al.

Gintonin stimulates gliotransmitter release in cortical primary astrocytes

“…For playing their role in metabolic and homeostatic functions of the nervous system, astrocytes contain gliotransmitters, which are used for intercellular communication between astrocytes and neurons [11]. In previous reports, we have shown gintonin enhanced synaptic transmission by stimulating the release of glutamate in hippocampal slices [9]. Gintonin also enhances NMDA receptor channel currents [14].…”

“…In addition, gintonin-mediated LPA receptor activation, and the following [Ca 2+ ] i transients, are linked to the regulation of intracellular Ca 2+ -dependent ion channels and receptors [8]. Further studies showed that gintonin mediated-[Ca 2+ ] i transients are also coupled to interneuron communication [9]. Although previous reports raise the possibility that gintonin-mediated [Ca 2+ ] i transients via LPA receptors play a key role in intra-and inter-neuronal communication, it has not been demonstrated that gintonin-mediated activation of G protein-coupled LPA receptors in primary astrocytes is coupled to the regulation of gliotransmitter release.…”

Gintonin Attenuates D-Galactose-Induced Hippocampal Senescence by Improving Long-Term Hippocampal Potentiation, Neurogenesis, and Cognitive Functions

“…S4). Moreover, gintonin increases hippocampal synaptic transmission via LPA1 receptor [33]. In addition, in vitro gintonin treatment of hippocampal neural progenitor cells may have stimulated their proliferation by increasing the number of LPA1 receptors in hippocampal NPCs due to enhanced LPA1 receptor and brain-derived neurotrophic factor expression [23,34].…”

Oral Administration of Gintonin Attenuates Cholinergic Impairments by Scopolamine, Amyloid-β Protein, and Mouse Model of Alzheimer’s Disease

“…In our previous work, we showed that ginseng contains a novel G protein-coupled lysophosphatidic acid (LPA) receptor ligand, gintonin ( Hwang et al, 2012a ; Pyo et al, 2011 ). Gintonin enhanced synaptic transmission in hippocampal slices through LPA receptor signaling pathways ( Park et al, 2015 ). We showed that gintonin is the active component of ginseng to attenuate AD-related neuropathies via activation of non-amyloidogenic pathways; gintonin significantly improved Aβ-induced cognitive dysfunctions in mice.…”