Channel-Mediated Tonic GABA Release from Glia

Tonic Inhibition Neuronal inhibition has recently drawn much attention; however, the mechanisms involved in tonic release of and the cellular source of the neurotransmitter involved, γ-aminobutyric acid (GABA), have been difficult to pin down. Lee et al. (p. 790, published online 23 September) showed that tonic release of GABA in the cerebellum occurs through the Bestrophin 1 anion channel of cerebellar astrocytes and Bergmann glial cells. These results confirm that glia can serve as a source of GABA for tonic inhibition of neurons and provide more evidence for interactions between neurons and glia cells that have implications for our understanding of brain-signaling mechanisms. The neurotransmitter GABA is tonically released from cells through an anion channel with an unusually large pore. Synaptic inhibition is based on both tonic and phasic release of the inhibitory transmitter γ-aminobutyric acid (GABA). Although phasic GABA release arises from Ca2+-dependent exocytosis from neurons, the mechanism of tonic GABA release is unclear. Here we report that tonic inhibition in the cerebellum is due to GABA being released from glial cells by permeation through the Bestrophin 1 (Best1) anion channel. We demonstrate that GABA directly permeates through Best1 to yield GABA release and that tonic inhibition is eliminated by silencing of Best1. Glial cells express both GABA and Best1, and selective expression of Best1 in glial cells, after preventing general expression of Best1, fully rescues tonic inhibition. Our results identify a molecular mechanism for tonic inhibition and establish a role for interactions between glia and neurons in mediating tonic inhibition.

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