Facilitation of neurotransmittcr release through activation of presynaptic P_2X receptors by endogenous ATP

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In aiming to clarify the interaction between astrocytes and neurons in native brain tissues through the intermediary of extracellular ATP-mediated signaling, I recorded postsynaptic currents of the neurons in the nucleus of the solitary tract (NTS) in transverse brainstem slices prepared from young Wistar rats and found the followings :1. Time- (100 ms) and space- (3 μm) delimited application of ATP using DMNPE-caged ATP and "flash-and-flush" application of laser beam onto dendrites of the neuron being recorded resulted in a marked increase in the frequency of spontaneous action potential-independent excitatory postsynaptic currents (EPSC). This glutamate release facilitation was almost completely abolished by PPADS (40 μM).2. The period of release facilitation was parallel to that of laser irradiation. The laser irradiation became ineffective after displacement of the beam by a few μm from the "hot.spot" on the dendrite. Under membrane potential recording without TTX but with Cd^<2+>, … More ATP uncaging resulted in an abrupt and short-lasting increase in the firing frequency of the recorded neuron.3. Fluoroacetate, a glia-specific toxin blocking TCA cycle, reduced the spontaneous EPSC frequency.4. A P_2Y_1 receptor agonist,2-methylthio-ADP, significantly increased EPSC frequency, an effect suppressed by a P_2X receptor blocker, trinitrophenyl ATP, and fluoroacetate.5. Trinitrophenyl ATP and A-317491, a P_2X_3-selective blocker, but not fluoroacetate and deletion of P_2X_4 protein abolished the release facilitation by a,β-methylene ATP.Altogether, these novel findings suggest that activation of astrocyte network in the NTS facilitates glutamate release though ATP release from astrocytes and subsequent activation of presynaptic P_2X_2/(3) receptors on the central terminals of the primary afferent fibers. This mechanism points to a possible ATP-mediated astrocyte-to-neuron signaling enabling astrocytes to promote excitatory transmission from the primary afferents to the second-order NTS neurons. Less