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GABA as a rising gliotransmitter.

Yoon BE, Lee CJ - Front Neural Circuits (2014)

Bottom Line: However, recent studies have shown that not only neurons but also astrocytes contain a considerable amount of GABA that can be released and activate GABA receptors in neighboring neurons.These exciting new findings for glial GABA raise further interesting questions about the source of GABA, its mechanism of release and regulation and the functional role of glial GABA.In this review, we highlight recent studies that identify the presence and release of GABA in glial cells, we show several proposed potential pathways for accumulation and modulation of glial intracellular and extracellular GABA content, and finally we discuss functional roles for glial GABA in the brain.

View Article: PubMed Central - PubMed

Affiliation: Department of Nanobiomedical Science, Dankook University Chungnam, South Korea.

ABSTRACT
Gamma-amino butyric acid (GABA) is the major inhibitory neurotransmitter that is known to be synthesized and released from GABAergic neurons in the brain. However, recent studies have shown that not only neurons but also astrocytes contain a considerable amount of GABA that can be released and activate GABA receptors in neighboring neurons. These exciting new findings for glial GABA raise further interesting questions about the source of GABA, its mechanism of release and regulation and the functional role of glial GABA. In this review, we highlight recent studies that identify the presence and release of GABA in glial cells, we show several proposed potential pathways for accumulation and modulation of glial intracellular and extracellular GABA content, and finally we discuss functional roles for glial GABA in the brain.

Show MeSH
Pathway showing GABA synthesis from putrescine. Astrocytes synthesize GABA from putrescine via monoamine oxidation. PAT: putrescine acetyltransferase; MAOB: monoamine oxidase B; ALDH2: aldehyde dehydrogenase 2.
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Figure 2: Pathway showing GABA synthesis from putrescine. Astrocytes synthesize GABA from putrescine via monoamine oxidation. PAT: putrescine acetyltransferase; MAOB: monoamine oxidase B; ALDH2: aldehyde dehydrogenase 2.

Mentions: Contrasting reports suggest that GABA is produced by another biosynthetic pathway, which is independent of GAD activity, but that requires putrescine as an initial substrate. This was first suggested in mouse and fish brain (Seiler and Askar, 1971; Seiler et al., 1973). In trout brain, following intraperitoneal and intracerebral injections of [1,4-14C]putrescine.2HCl, GABA was shown to be formed in vivo, via a pathway that does not have glutamic acid as an intermediate. After intracerebral injections of [1-14C] GABA, a half-life of 7 h was obtained for GABA. This slow turnover rate for GABA in trout brain may help to further explain the ineffectiveness of the glutamate decarboxylase inhibitors in lowering the GABA content of fish brain within a few hours (Seiler et al., 1973). Putrescine concentrations can be quantitatively estimated in tissue and have been determined in mouse brain and liver (Seiler and Askar, 1971). This polyamine involved pathway for GABA synthesis was tested in mouse neuroblastoma cells (Kremzner et al., 1975). Polyamine metabolism in cultured mouse neuroblastoma cells was studied with the aim of synthesizing GABA from putrescine and putreanine from spermidine. It was shown that neuroblastoma cells, in the presence of a complete culture medium containing calf serum, readily metabolized [14C] putrescine to GABA. The rate of synthesis is similar to that for the synthesis of spermidine from putrescine. In the absence of serum, the conversion of putrescine to GABA is minimal. In the presence of serum, GABA formation is completely inhibited by the diamine oxidase inhibitor aminoguanidine. Synthesized GABA is not readily metabolized to succinate or homocarnosine. Mouse neuroblastoma cells metabolized [14C] ornithine to putrescine, GABA, and spermidine. Spermidine was metabolized to putrescine, putreanine and spermine (Kremzner et al., 1975). This is the monoamine oxidase pathway of putrescine (Figure 2). Cultured O2A glial progenitor cells of the optic nerve were able to synthesize GABA from putrescine. In these cells, there is no detectable GAD expression, but a strong GABA immunoreactivity was seen and HPLC measurements revealed an increased quantity of GABA in a putrescine-enriched medium (Barres et al., 1990). Glial cell GABA may also be involved in some pathological conditions. A comparison between GABA formation in primary cultured astrocytes from epileptic and normal mice showed that the rate of GABA production from radioactive putrescine was four times higher in epileptic than in normal mice (Laschet et al., 1992). Moreover, after transiently occluding the carotid arteries of adult gerbils, the GFAP immunoreactivity increased in the damaged forebrain tissue and reactive astrocytes were labeled with GABA, but not with GAD antisera. This GABA immunoreactivity persisted in ischemic animals for up to 3 months without GAD activity (Lin et al., 1993). It has recently been reported that glial monoamine oxidase B (MAOB) is the GABA synthesizing enzyme that mediates tonic GABA release. In the cerebellum and striatum of adult mice, general gene-silencing or knockout of MAOB, or treatment with selegiline, eliminated tonic GABA currents recorded from granule neurons and medium spiny neurons. Glial specific rescue of MAOB resulted in a complete rescue of tonic GABA currents. These results identify MAOB as a key synthesizing enzyme of glial GABA, which is released via the Best1 channel to mediate tonic inhibition in the brain (Yoon et al., 2014).


GABA as a rising gliotransmitter.

Yoon BE, Lee CJ - Front Neural Circuits (2014)

Pathway showing GABA synthesis from putrescine. Astrocytes synthesize GABA from putrescine via monoamine oxidation. PAT: putrescine acetyltransferase; MAOB: monoamine oxidase B; ALDH2: aldehyde dehydrogenase 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4269106&req=5

Figure 2: Pathway showing GABA synthesis from putrescine. Astrocytes synthesize GABA from putrescine via monoamine oxidation. PAT: putrescine acetyltransferase; MAOB: monoamine oxidase B; ALDH2: aldehyde dehydrogenase 2.
Mentions: Contrasting reports suggest that GABA is produced by another biosynthetic pathway, which is independent of GAD activity, but that requires putrescine as an initial substrate. This was first suggested in mouse and fish brain (Seiler and Askar, 1971; Seiler et al., 1973). In trout brain, following intraperitoneal and intracerebral injections of [1,4-14C]putrescine.2HCl, GABA was shown to be formed in vivo, via a pathway that does not have glutamic acid as an intermediate. After intracerebral injections of [1-14C] GABA, a half-life of 7 h was obtained for GABA. This slow turnover rate for GABA in trout brain may help to further explain the ineffectiveness of the glutamate decarboxylase inhibitors in lowering the GABA content of fish brain within a few hours (Seiler et al., 1973). Putrescine concentrations can be quantitatively estimated in tissue and have been determined in mouse brain and liver (Seiler and Askar, 1971). This polyamine involved pathway for GABA synthesis was tested in mouse neuroblastoma cells (Kremzner et al., 1975). Polyamine metabolism in cultured mouse neuroblastoma cells was studied with the aim of synthesizing GABA from putrescine and putreanine from spermidine. It was shown that neuroblastoma cells, in the presence of a complete culture medium containing calf serum, readily metabolized [14C] putrescine to GABA. The rate of synthesis is similar to that for the synthesis of spermidine from putrescine. In the absence of serum, the conversion of putrescine to GABA is minimal. In the presence of serum, GABA formation is completely inhibited by the diamine oxidase inhibitor aminoguanidine. Synthesized GABA is not readily metabolized to succinate or homocarnosine. Mouse neuroblastoma cells metabolized [14C] ornithine to putrescine, GABA, and spermidine. Spermidine was metabolized to putrescine, putreanine and spermine (Kremzner et al., 1975). This is the monoamine oxidase pathway of putrescine (Figure 2). Cultured O2A glial progenitor cells of the optic nerve were able to synthesize GABA from putrescine. In these cells, there is no detectable GAD expression, but a strong GABA immunoreactivity was seen and HPLC measurements revealed an increased quantity of GABA in a putrescine-enriched medium (Barres et al., 1990). Glial cell GABA may also be involved in some pathological conditions. A comparison between GABA formation in primary cultured astrocytes from epileptic and normal mice showed that the rate of GABA production from radioactive putrescine was four times higher in epileptic than in normal mice (Laschet et al., 1992). Moreover, after transiently occluding the carotid arteries of adult gerbils, the GFAP immunoreactivity increased in the damaged forebrain tissue and reactive astrocytes were labeled with GABA, but not with GAD antisera. This GABA immunoreactivity persisted in ischemic animals for up to 3 months without GAD activity (Lin et al., 1993). It has recently been reported that glial monoamine oxidase B (MAOB) is the GABA synthesizing enzyme that mediates tonic GABA release. In the cerebellum and striatum of adult mice, general gene-silencing or knockout of MAOB, or treatment with selegiline, eliminated tonic GABA currents recorded from granule neurons and medium spiny neurons. Glial specific rescue of MAOB resulted in a complete rescue of tonic GABA currents. These results identify MAOB as a key synthesizing enzyme of glial GABA, which is released via the Best1 channel to mediate tonic inhibition in the brain (Yoon et al., 2014).

Bottom Line: However, recent studies have shown that not only neurons but also astrocytes contain a considerable amount of GABA that can be released and activate GABA receptors in neighboring neurons.These exciting new findings for glial GABA raise further interesting questions about the source of GABA, its mechanism of release and regulation and the functional role of glial GABA.In this review, we highlight recent studies that identify the presence and release of GABA in glial cells, we show several proposed potential pathways for accumulation and modulation of glial intracellular and extracellular GABA content, and finally we discuss functional roles for glial GABA in the brain.

View Article: PubMed Central - PubMed

Affiliation: Department of Nanobiomedical Science, Dankook University Chungnam, South Korea.

ABSTRACT
Gamma-amino butyric acid (GABA) is the major inhibitory neurotransmitter that is known to be synthesized and released from GABAergic neurons in the brain. However, recent studies have shown that not only neurons but also astrocytes contain a considerable amount of GABA that can be released and activate GABA receptors in neighboring neurons. These exciting new findings for glial GABA raise further interesting questions about the source of GABA, its mechanism of release and regulation and the functional role of glial GABA. In this review, we highlight recent studies that identify the presence and release of GABA in glial cells, we show several proposed potential pathways for accumulation and modulation of glial intracellular and extracellular GABA content, and finally we discuss functional roles for glial GABA in the brain.

Show MeSH