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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
Presence of GABA in glial cells in various brain regions of GFAP-GFP mice. Gamma-amino butyric acid is present in the cerebellum, hippocampus and thalamus, though the GABA-containing portion of the glial cell differs between brain regions. Gamma-amino butyric acid does not co-localize much with GFAP-GFP staining in the hippocampus compared to the cerebellar cortex.
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Figure 1: Presence of GABA in glial cells in various brain regions of GFAP-GFP mice. Gamma-amino butyric acid is present in the cerebellum, hippocampus and thalamus, though the GABA-containing portion of the glial cell differs between brain regions. Gamma-amino butyric acid does not co-localize much with GFAP-GFP staining in the hippocampus compared to the cerebellar cortex.

Mentions: Initial reports showed that glia contain considerable amounts of GABA under normal physiological conditions. Astrocytes in brainstem were labeled with an anti-GABA antibody at the level of the soma, in the processes surrounding neurons and in astrocyte endfeet in contact with blood vessels (Blomqvist and Broman, 1988). The presence of GABA in glial cells has been studied extensively in rat optic nerve. In cell cultures of rat optic nerve, 1 week after plating, O2A-oligodendrocyte progenitor cells, type 2 astrocytes and differentiated oligodendrocytes were shown to express GABA (Barres et al., 1990). Gamma-amino butyric acid was localized using immunofluorescence with an astrocytic marker, glial fibrillary acidic protein (GFAP), in developing rat optic nerve from embryonic day 20 to postnatal day 28 (Lake, 1992). A transient increase and gradual decrease of GABA in glial cells after postnatal day 20 was reported by immunostaining and high pressure liquid chromatography (HPLC; Ochi et al., 1993). This study showed the developmental time course of astrocytic GABA expression in rat optic nerve. Gamma-amino butyric acid immunostaining was carried out on cultured astrocytes, and on whole optic nerve and GABA immunoreactivity was localized by GFAP staining. Gamma-amino butyric acid staining was most intense in early neonatal optic nerve and became attenuated over 3 weeks of postnatal development. Staining was pronounced in the astrocyte cell bodies and processes but not in the nucleus. There was a paucity of GABA immunoreactivity by postnatal day 20, both in cultured cells and in whole optic nerve. A biochemical assay for optic nerve GABA using HPLC indicated a relatively high concentration of GABA in the neonate, which rapidly attenuated over the first three postnatal weeks (Ochi et al., 1993). Gamma-amino butyric acid immunoreactivity was also observed in glial cells from the adult rat cerebellum (Martínez-Rodríguez et al., 1993). Both GABA- and Glutamic acid decarboxylase (GAD)-immunoreactivities were observed within dendrites and glial cells using different antisera obtained from rabbits immunized with GABA, baclofen and GAD. These results suggested a possible extrasynaptic release of GABA. However, these early findings had been almost forgotten by brain research scientists until recently (Angulo et al., 2008). We ourselves have recently reported strong GABA immunoreactivities in Bergmann glial cells and lamellar astrocytes of the mouse cerebellum using a commercially available anti-GABA antibody in GFAP-GFP transgenic mice (Lee et al., 2010). We have suggested that the amount of glial GABA is variable depending on different brain regions (Figure 1) and that it positively correlates with the degree of tonic inhibition current (Yoon et al., 2011). For example, glial GABA as evidenced by GABA immunoreactivity was high in the cerebellum and correlated well with a significant level of tonic inhibition current, whereas GABA immunoreactivity was very low in the hippocampus CA1 region with a low level of tonic inhibition current (Yoon et al., 2011). These results suggested that some regulatory mechanism exists to control the level of intracellular GABA in astrocytes. More recently, GABA immunoparticles were localized by electron microscopy in synaptic terminals with symmetric synapses as well as in astrocytes from CA1 and CA3 areas, the stratum radiatum and in the dentate gyrus (Le Meur et al., 2012). This would seem to indicate that a large proportion of hippocampal astrocytes contain the inhibitory transmitter GABA. In addition, immunoreactivity for GABA, GAD65, GAD67 and Bestrophin-1 (Best1), a GABA-permeable channel, has been observed in the meninges and the choroid plexus, implying a non-neuronal source for GABA in the developing mouse brain (Tochitani and Kondo, 2013).


GABA as a rising gliotransmitter.

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

Presence of GABA in glial cells in various brain regions of GFAP-GFP mice. Gamma-amino butyric acid is present in the cerebellum, hippocampus and thalamus, though the GABA-containing portion of the glial cell differs between brain regions. Gamma-amino butyric acid does not co-localize much with GFAP-GFP staining in the hippocampus compared to the cerebellar cortex.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Presence of GABA in glial cells in various brain regions of GFAP-GFP mice. Gamma-amino butyric acid is present in the cerebellum, hippocampus and thalamus, though the GABA-containing portion of the glial cell differs between brain regions. Gamma-amino butyric acid does not co-localize much with GFAP-GFP staining in the hippocampus compared to the cerebellar cortex.
Mentions: Initial reports showed that glia contain considerable amounts of GABA under normal physiological conditions. Astrocytes in brainstem were labeled with an anti-GABA antibody at the level of the soma, in the processes surrounding neurons and in astrocyte endfeet in contact with blood vessels (Blomqvist and Broman, 1988). The presence of GABA in glial cells has been studied extensively in rat optic nerve. In cell cultures of rat optic nerve, 1 week after plating, O2A-oligodendrocyte progenitor cells, type 2 astrocytes and differentiated oligodendrocytes were shown to express GABA (Barres et al., 1990). Gamma-amino butyric acid was localized using immunofluorescence with an astrocytic marker, glial fibrillary acidic protein (GFAP), in developing rat optic nerve from embryonic day 20 to postnatal day 28 (Lake, 1992). A transient increase and gradual decrease of GABA in glial cells after postnatal day 20 was reported by immunostaining and high pressure liquid chromatography (HPLC; Ochi et al., 1993). This study showed the developmental time course of astrocytic GABA expression in rat optic nerve. Gamma-amino butyric acid immunostaining was carried out on cultured astrocytes, and on whole optic nerve and GABA immunoreactivity was localized by GFAP staining. Gamma-amino butyric acid staining was most intense in early neonatal optic nerve and became attenuated over 3 weeks of postnatal development. Staining was pronounced in the astrocyte cell bodies and processes but not in the nucleus. There was a paucity of GABA immunoreactivity by postnatal day 20, both in cultured cells and in whole optic nerve. A biochemical assay for optic nerve GABA using HPLC indicated a relatively high concentration of GABA in the neonate, which rapidly attenuated over the first three postnatal weeks (Ochi et al., 1993). Gamma-amino butyric acid immunoreactivity was also observed in glial cells from the adult rat cerebellum (Martínez-Rodríguez et al., 1993). Both GABA- and Glutamic acid decarboxylase (GAD)-immunoreactivities were observed within dendrites and glial cells using different antisera obtained from rabbits immunized with GABA, baclofen and GAD. These results suggested a possible extrasynaptic release of GABA. However, these early findings had been almost forgotten by brain research scientists until recently (Angulo et al., 2008). We ourselves have recently reported strong GABA immunoreactivities in Bergmann glial cells and lamellar astrocytes of the mouse cerebellum using a commercially available anti-GABA antibody in GFAP-GFP transgenic mice (Lee et al., 2010). We have suggested that the amount of glial GABA is variable depending on different brain regions (Figure 1) and that it positively correlates with the degree of tonic inhibition current (Yoon et al., 2011). For example, glial GABA as evidenced by GABA immunoreactivity was high in the cerebellum and correlated well with a significant level of tonic inhibition current, whereas GABA immunoreactivity was very low in the hippocampus CA1 region with a low level of tonic inhibition current (Yoon et al., 2011). These results suggested that some regulatory mechanism exists to control the level of intracellular GABA in astrocytes. More recently, GABA immunoparticles were localized by electron microscopy in synaptic terminals with symmetric synapses as well as in astrocytes from CA1 and CA3 areas, the stratum radiatum and in the dentate gyrus (Le Meur et al., 2012). This would seem to indicate that a large proportion of hippocampal astrocytes contain the inhibitory transmitter GABA. In addition, immunoreactivity for GABA, GAD65, GAD67 and Bestrophin-1 (Best1), a GABA-permeable channel, has been observed in the meninges and the choroid plexus, implying a non-neuronal source for GABA in the developing mouse brain (Tochitani and Kondo, 2013).

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