Slc38a1 Conveys Astroglia-Derived Glutamine into GABAergic Interneurons for Neurotransmitter GABA Synthesis
GABA signaling is involved in a wide range of neuronal functions, such as synchronization of action potential firing, synaptic plasticity and neuronal development. Sustained GABA signaling requires efficient mechanisms for the replenishment of the neurotransmitter pool of GABA. The prevailing theory...
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MDPI AG
2020-07-01
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| Online Access: | https://www.mdpi.com/2073-4409/9/7/1686 |
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| author | Tayyaba Qureshi Mona Bjørkmo Kaja Nordengen Vidar Gundersen Tor Paaske Utheim Leiv Otto Watne Jon Storm-Mathisen Bjørnar Hassel Farrukh Abbas Chaudhry |
| author_facet | Tayyaba Qureshi Mona Bjørkmo Kaja Nordengen Vidar Gundersen Tor Paaske Utheim Leiv Otto Watne Jon Storm-Mathisen Bjørnar Hassel Farrukh Abbas Chaudhry |
| author_sort | Tayyaba Qureshi |
| collection | DOAJ |
| description | GABA signaling is involved in a wide range of neuronal functions, such as synchronization of action potential firing, synaptic plasticity and neuronal development. Sustained GABA signaling requires efficient mechanisms for the replenishment of the neurotransmitter pool of GABA. The prevailing theory is that exocytotically released GABA may be transported into perisynaptic astroglia and converted to glutamine, which is then shuttled back to the neurons for resynthesis of GABA—i.e., the glutamate/GABA-glutamine (GGG) cycle. However, an unequivocal demonstration of astroglia-to-nerve terminal transport of glutamine and the contribution of astroglia-derived glutamine to neurotransmitter GABA synthesis is lacking. By genetic inactivation of the amino acid transporter Solute carrier 38 member a1 (Slc38a1)—which is enriched on parvalbumin<sup>+</sup> GABAergic neurons—and by intraperitoneal injection of radiolabeled acetate (which is metabolized to glutamine in astroglial cells), we show that Slc38a1 mediates import of astroglia-derived glutamine into GABAergic neurons for synthesis of GABA. In brain slices, we demonstrate the role of Slc38a1 for the uptake of glutamine specifically into GABAergic nerve terminals for the synthesis of GABA depending on demand and glutamine supply. Thus, while leaving room for other pathways, our study demonstrates a key role of Slc38a1 for newly formed GABA, in harmony with the existence of a GGG cycle. |
| first_indexed | 2024-03-09T06:10:07Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T06:10:07Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-2591aaba31114017a0c80c1e5d93b77d2023-12-03T11:58:50ZengMDPI AGCells2073-44092020-07-0197168610.3390/cells9071686Slc38a1 Conveys Astroglia-Derived Glutamine into GABAergic Interneurons for Neurotransmitter GABA SynthesisTayyaba Qureshi0Mona Bjørkmo1Kaja Nordengen2Vidar Gundersen3Tor Paaske Utheim4Leiv Otto Watne5Jon Storm-Mathisen6Bjørnar Hassel7Farrukh Abbas Chaudhry8Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, NorwayDepartment of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, NorwayDepartment of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, NorwayDepartment of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, NorwayDepartment of Plastic and Reconstructive Surgery, Oslo University Hospital, 0424 Oslo, NorwayDepartment of Geriatric Medicine, Oslo University Hospital, 0424 Oslo, NorwayDepartment of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, NorwayDepartment of Neurohabilitation, Oslo University Hospital and University of Oslo, 0424 Oslo, NorwayDepartment of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, NorwayGABA signaling is involved in a wide range of neuronal functions, such as synchronization of action potential firing, synaptic plasticity and neuronal development. Sustained GABA signaling requires efficient mechanisms for the replenishment of the neurotransmitter pool of GABA. The prevailing theory is that exocytotically released GABA may be transported into perisynaptic astroglia and converted to glutamine, which is then shuttled back to the neurons for resynthesis of GABA—i.e., the glutamate/GABA-glutamine (GGG) cycle. However, an unequivocal demonstration of astroglia-to-nerve terminal transport of glutamine and the contribution of astroglia-derived glutamine to neurotransmitter GABA synthesis is lacking. By genetic inactivation of the amino acid transporter Solute carrier 38 member a1 (Slc38a1)—which is enriched on parvalbumin<sup>+</sup> GABAergic neurons—and by intraperitoneal injection of radiolabeled acetate (which is metabolized to glutamine in astroglial cells), we show that Slc38a1 mediates import of astroglia-derived glutamine into GABAergic neurons for synthesis of GABA. In brain slices, we demonstrate the role of Slc38a1 for the uptake of glutamine specifically into GABAergic nerve terminals for the synthesis of GABA depending on demand and glutamine supply. Thus, while leaving room for other pathways, our study demonstrates a key role of Slc38a1 for newly formed GABA, in harmony with the existence of a GGG cycle.https://www.mdpi.com/2073-4409/9/7/1686astrocyte-neuron shuttleGABAglutamateglutamine transporterinterneuronneurotransmitter replenishment |
| spellingShingle | Tayyaba Qureshi Mona Bjørkmo Kaja Nordengen Vidar Gundersen Tor Paaske Utheim Leiv Otto Watne Jon Storm-Mathisen Bjørnar Hassel Farrukh Abbas Chaudhry Slc38a1 Conveys Astroglia-Derived Glutamine into GABAergic Interneurons for Neurotransmitter GABA Synthesis Cells astrocyte-neuron shuttle GABA glutamate glutamine transporter interneuron neurotransmitter replenishment |
| title | Slc38a1 Conveys Astroglia-Derived Glutamine into GABAergic Interneurons for Neurotransmitter GABA Synthesis |
| title_full | Slc38a1 Conveys Astroglia-Derived Glutamine into GABAergic Interneurons for Neurotransmitter GABA Synthesis |
| title_fullStr | Slc38a1 Conveys Astroglia-Derived Glutamine into GABAergic Interneurons for Neurotransmitter GABA Synthesis |
| title_full_unstemmed | Slc38a1 Conveys Astroglia-Derived Glutamine into GABAergic Interneurons for Neurotransmitter GABA Synthesis |
| title_short | Slc38a1 Conveys Astroglia-Derived Glutamine into GABAergic Interneurons for Neurotransmitter GABA Synthesis |
| title_sort | slc38a1 conveys astroglia derived glutamine into gabaergic interneurons for neurotransmitter gaba synthesis |
| topic | astrocyte-neuron shuttle GABA glutamate glutamine transporter interneuron neurotransmitter replenishment |
| url | https://www.mdpi.com/2073-4409/9/7/1686 |
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