Glial Cell Inhibition of Neurons by Release of ATP

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Abstract
ATP is released by neurons and functions as a neurotransmitter and modulator in the CNS. Here I show that ATP released from glial cells can also serve as a potent neuromodulator, inhibiting neurons in the retina of the rat. Activation of glial cells by focal ejection of ATP, ATPγS, dopamine, thrombin, or lysophosphatidic acid or by mechanical stimulation evoked hyperpolarizing responses and outward currents in a subset of retinal ganglion cells by increasing a Ba2+-sensitive K+ conductance in the neurons. This glia-evoked inhibition reduced the firing rate of those neurons that displayed spontaneous spike activity. The inhibition was abolished by the A1 adenosine receptor antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine) (10 nm) and was reduced by the ecto-ATPase inhibitor ARL-67156 (6-N,N-diethyl-d-β,γ-dibromomethyleneATP) (50 μm) and by the ectonucleotidase inhibitor AOPCP [adenosine-5′-O-(α,β-methylene)-diphosphonate] (250 μm). Selective activation of retinal glial cells demonstrated that Müller cells, but not astrocytes, mediate the inhibition. ATP release from Müller cells into the inner plexiform layer of the retina was shown using the luciferin–luciferase chemiluminescence assay. These findings demonstrate that activated glial cells can inhibit neurons in the retina by the release of ATP, which is converted to adenosine by ectoenzymes and subsequently activates neuronal adenosine receptors. The results lend support to the hypothesis that glial cells play an active role in information processing in the CNS.