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The Journal of Neuroscience, September 29, 2004, 24(39):8606-8620; doi:10.1523/JNEUROSCI.2660-04.2004

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Cellular/Molecular
ATP Excites Interneurons and Astrocytes to Increase Synaptic Inhibition in Neuronal Networks

David N. Bowser and Baljit S. Khakh

Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom

We investigated the role of extracellular ATP at astrocytes and inhibitory GABAergic interneurons in the stratum radiatum area of the mouse hippocampus. We show that exogenously applied ATP increased astrocyte intracellular Ca²⁺ levels and depolarized all calbindinand calretinin-positive interneurons in the stratum radiatum region of mouse hippocampus, leading to action potential firing and enhanced synaptic inhibition onto the postsynaptic targets of interneurons. Electrophysiological, pharmacological, and immunostaining studies suggested that the effect of ATP on interneurons was mediated by P2Y₁ receptors, and that the depolarization of interneurons was caused by the concomitant reduction and activation of potassium and nonselective cationic conductances, respectively. Electrical stimulation of the Schaffer collaterals and perforant path, as well as local stimulation within the stratum radiatum, evoked increases in intracellular Ca²⁺ in astrocytes. Facilitation of GABAergic IPSCs onto interneurons also occurred during electrical stimulation. Both the stimulation-evoked increases in astrocyte Ca²⁺ levels and facilitation of GABAergic IPSCs were sensitive to antagonists of P2Y₁ receptors and mimicked by exogenous P2Y₁ receptor agonists, suggesting that endogenously released ATP can activate P2Y receptors on both astrocytes and interneurons. Overall, our data are consistent with the hypothesis that ATP released from neurons and astrocytes acts on P2Y₁ receptors to excite interneurons, resulting in increased synaptic inhibition within intact hippocampal circuits.

Key words: purinergic; interneuron; astrocyte; inhibition; IPSP; hippocampus; P2Y; P2X

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Received March 30, 2004; revised August 17, 2004; accepted August 18, 2004.

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