Abstract
BackgroundAccumulating evidence suggests that glial signalling is activated by different brain functions. However, knowledge regarding molecular mechanisms of activation or their relation to neuronal activity is limited. The purpose of the present study is to identify the characteristics of ATP-evoked glial signalling in the brain reward area, the nucleus accumbens (NAc), and thereby to explore the action of citric acid cycle intermediate succinate (SUC).ResultsWe described the burst-like propagation of Ca2+ transients evoked by ATP in acute NAc slices from rat brain. Co-localization of the ATP-evoked Ca2+ signalling with immunoreactivities of the astroglia-specific gap junction forming channel protein connexin43 (Cx43) and the glial fibrillary acidic protein (GFAP) indicated that the responsive cells were a subpopulation of Cx43 and GFAP immunoreactive astrocytes. The ATP-evoked Ca2+ transients were present under the blockade of neuronal activity, but were inhibited by Ca2+ store depletion and antagonism of the G protein coupled purinergic P2Y1 receptor subtype-specific antagonist MRS2179. Similarly, Ca2+ transients evoked by the P2Y1 receptor subtype-specific agonist 2-(Methylthio)adenosine 5'-diphosphate were also blocked by MRS2179. These characteristics implied that intercellular Ca2+ signalling originated from the release of Ca2+ from internal stores, triggered by the activation of P2Y1 receptors. Inhibition by the gap junction blockers carbenoxolone and flufenamic acid and by an antibody raised against the gating-associated segment of Cx43 suggested that intercellular Ca2+ signalling proceeded through gap junctions. We demonstrated for the first time that extracellular SUC also evoked Ca2+ transients (EC50 = 50-60 μM) in about 15% of the ATP-responsive NAc astrocytes. By contrast to glial cells, electrophysiologically identified NAc neurons surrounded by ATP-responsive astrocytes were not activated simultaneously.ConclusionsWe concluded, therefore, that ATP- and SUC-sensitive Ca2+ transients appear to represent a signalling layer independent of NAc neurons. This previously unrecognised glial action of SUC, a major cellular energy metabolite, may play a role in linking metabolism to Ca2+ signalling in astrocytic networks under physiological and pathological conditions such as exercise and metabolic diseases.
Highlights
Accumulating evidence suggests that glial signalling is activated by different brain functions
In order to study the effect and functional significance of SUC on the Ca2+ homeostasis of nucleus accumbens (NAc) astrocytes, we considered that the Ca2+ bursting activity was found ATPresponsive in vivo, i.e. in Bergmann glia networks activated by the motor behaviour of the awaken animal
We asked if connexin 43 (Cx43)-positive NAc astrocytes were responded to local administration of ATP by Ca2+ transients
Summary
Accumulating evidence suggests that glial signalling is activated by different brain functions. The purpose of the present study is to identify the characteristics of ATP-evoked glial signalling in the brain reward area, the nucleus accumbens (NAc), and thereby to explore the action of citric acid cycle intermediate succinate (SUC). In astrocytes of the brain reward area, the nucleus accumbens (NAc; [1]), g-hydroxybutyric acid (GHB; [2]) evoked intracellular store-reliant Ca2+ transients, independently of neuronal activity [3]. In order to study the effect and functional significance of SUC on the Ca2+ homeostasis of NAc astrocytes, we considered that the Ca2+ bursting activity was found ATPresponsive in vivo, i.e. in Bergmann glia networks activated by the motor behaviour of the awaken animal [7]. ATP-evoked Ca2+ bursts have been characterised by using of various drugs and agents, including gap-junction inhibitors (CBX, flufenamic acid: FFA), an antibody raised against the gating peptide segment of
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