Calcium signals in the nucleus accumbens: Activation of astrocytes by ATP and succinate

BACKGROUND: Accumulating 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). RESULTS: We described the burst-like propagation of Ca(2+ )transients evoked by ATP in acute NAc slices from rat brain. Co-localization of the ATP-evoked Ca(2+ )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 Ca(2+ )transients were present under the blockade of neuronal activity, but were inhibited by Ca(2+ )store depletion and antagonism of the G protein coupled purinergic P2Y(1 )receptor subtype-specific antagonist MRS2179. Similarly, Ca(2+ )transients evoked by the P2Y(1 )receptor subtype-specific agonist 2-(Methylthio)adenosine 5'-diphosphate were also blocked by MRS2179. These characteristics implied that intercellular Ca(2+ )signalling originated from the release of Ca(2+ )from internal stores, triggered by the activation of P2Y(1 )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 Ca(2+ )signalling proceeded through gap junctions. We demonstrated for the first time that extracellular SUC also evoked Ca(2+ )transients (EC(50 )= 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. CONCLUSIONS: We concluded, therefore, that ATP- and SUC-sensitive Ca(2+ )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 Ca(2+ )signalling in astrocytic networks under physiological and pathological conditions such as exercise and metabolic diseases.