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Astrocyte derived ATP differentially modulates the excitability of hippocampal neurons

Astrocyte derived ATP, together with its degradation product adenosine, is known to regulate synaptic transmission through a presynaptic mechanism. However, little attention has been paid to the direct effect of gliotransmitters on the excitability of neuronal networks beyond synapses. Here, we showed that selective stimulation of astrocytes expressing channelrhodopsin 2 in the CA1 area specifically increased the firing frequency of CCK positive interneurons and decreased the firing rate of pyramidal neurons, but did not affect the activity of parvalbumin positive interneurons, phenomena mimicked by exogenously applied ATP. Further evidence indicated that ATP induced increase and decrease of excitability were caused respectively by P2Y1 receptor mediated inhibition of a TASK3 (tandem pore domain acid sensitive potassium channel 3) like two pore domain potassium channel (K2P) and A1 receptor mediated opening of a G protein coupled inwardly rectifying potassium channel (GIRK). Single cell RT PCR and immunostaining showed that P2Y1 and A1 receptors were differentially expressed on interneurons and pyramidal neurons. Application of antagonists to P2Y1 and A1 receptors disclosed the purine mediated tonic excitation of interneurons and inhibition of pyramidal neurons, respectively. Moreover, activation of ChR2 expressing astrocytes reduced the power of kainate induced hippocampal gamma oscillation. Thus, through distinct receptor subtypes coupled with different K+ channels, astrocyte derived ATP differentially modulates the excitability of different types of neurons and efficiently controls the activity of neuronal network.