Glial GABA, synthesized by monoamine oxidase B, mediates tonic inhibition

Abstract

Key pointsr Here we show that glial gamma aminobutyric acid (GABA) is produced by monoamine oxidase B (MAOB), utilizing a polyamine, putrescine.r The concentration of GABA in Bergmann glial cells is estimated to be around 5-10 mM. r General gene silencing of MAOB resulted in elimination of tonic GABA currents recorded from granule cells in the cerebellum and medium spiny neurons (MSN) in the striatum.r Glial-specific rescue of MAOB resulted in complete restoration of tonic GABA currents. r Our results identify MAOB as a synthesizing enzyme of glial GABA, which is released to mediate tonic inhibition in the cerebellum and striatum.Abstract GABA is the major inhibitory transmitter in the brain and is released not only from a subset of neurons but also from glia. Although neuronal GABA is well known to be synthesized by glutamic acid decarboxylase (GAD), the source of glial GABA is unknown. After estimating the concentration of GABA in Bergmann glia to be around 5-10 mM by immunogold electron microscopy, we demonstrate that GABA production in glia requires MAOB, a key enzyme in the putrescine degradation pathway. In cultured cerebellar glia, both Ca 2+ -induced and tonic GABA release are significantly reduced by both gene silencing of MAOB and the MAOB inhibitor selegiline. In the cerebellum and striatum of adult mice, general gene silencing, knock out of MAOB or selegiline treatment resulted in elimination of tonic GABA currents recorded from granule neurons and medium spiny neurons. Glial-specific rescue of MAOB resulted in complete rescue of tonic GABA currents. Our results identify MAOB as a key synthesizing enzyme of glial GABA, which is released via bestrophin 1 (Best1) channel to mediate tonic inhibition in the brain.

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Selective transport of neurotransmitters and modulators by distinct volume-regulated LRRC8 anion channels

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“…Astrocytes have been revealed as one of the main sources of extrasynaptic GABA that accounts for tonic inhibition (for a review see [Yoon & Lee, ]). Remarkably, astrocytes can synthesize GABA from the polyamine putrescine using an alternative pathway implying monoamine oxidase B (MAOB) (Heja et al, ; Yoon et al, ). Alterations in MAOB activity impaired tonic inhibition via GAT‐ or Bestrophin‐1 (Best1)‐dependent GABA release (Heja et al, ; Yoon et al, ).…”