Channel-Mediated Tonic GABA Release from Glia

Abstract

Synaptic inhibition is based on both tonic and phasic release of the inhibitory transmitter γ-aminobutyric acid (GABA). Although phasic GABA release arises from Ca(2+)-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.

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

“…Hence, GABA A receptors can generate two types of current, depending on their location and subunit composition: the first type is the classic synaptic phasic (or 'transient') current that results from the release of GABA from synaptic vesicles in the synaptic cleft; the second type is a tonic ('always on') current that is caused by GABA A receptors responding to low levels of ambient GABA (Farrant and Nusser, 2005). Recently, it has been demonstrated that GABA leading to tonic activation of GABA A receptors is released, at least in cerebellum, from glial cells by permeation through bestropin 1 anion channels (Lee et al, 2010). It has also been reported that taurine can activate extrasynaptic GABA A receptors in the mouse ventrobasal thalamus thus reducing the excitability of thalamocortical relay neurons (Jia et al, 2008).…”

Glia and gliotransmitters on carbon nanotubes

“…GABA acts at inhibitory synapses in the brain by binding to specific receptors in pre- and post-synaptic neurons. Recent studies have demonstrated a robust release of GABA from glial cells in human astrocytes and acute brain slices [18,41]. Furthermore, astrocytic release of GABA can cause tonic inhibition in several brain regions, including the thalamus and cerebellum [42,43].…”

“…Tonic inhibition orginates from the sustained activation of high affinity GABA receptors by ambient GABA [22]. In the cerebellum, some studies have reported that a Ca 2+ -activated anion channel, Best1, mediates tonic inhibition by releasing GABA through direct permeation [18,43]. In addition, glial MAOB is a key synthesizing enzyme of GABA and converts putrescine to GABA in the mitochondria of astrocytes [44].…”

“…Among the various types of glia, astrocytes occupy the greatest proportion (about 50%) in the brain and can make bidirectional communication with neurons. Also, astrocytes express diverse receptors for corresponding neurotransmitters and release gliotransmitters, including glutamate, adenosine triphosphate (ATP), and γ-amino butyric acid (GABA) [17,18]. Gliotransmitters are released from astrocytes and play important roles in modulating neuronal activity through neuron–glia interaction.…”

“…In particular, gliotransmission is also related to function of neural activity and brain disease, which is an abnormality of neural networks. In normal conditions, tonic inhibition dominates more for regulating neuronal excitability than phasic inhibition, and astrocytic GABA mediates tonic inhibition through a direct permeable channel, bestrophin 1 (Best1) [18,22]. Reactive astrocytic GABA expressed high contents in the dentate gyrus, which resulted in impairment of LTP and memory by elevating tonic inhibition in an Alzheimer’s disease (AD) mouse model [23].…”