Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway.
Department of Plastic and Reconstructive Surgery, Oslo University Hospital, 0424 Oslo, Norway.
Cells. 2020 Jul 13;9(7):1686. doi: 10.3390/cells9071686.
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 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.
GABA 信号转导参与广泛的神经元功能，例如动作电位发放的同步、突触可塑性和神经元发育。持续的 GABA 信号转导需要有效的机制来补充 GABA 神经递质池。流行的理论是，胞吐释放的 GABA 可能被运送到突触周围的星形胶质细胞中，并转化为谷氨酰胺，然后再被转运回神经元中，用于 GABA 的再合成，即谷氨酸/GABA-谷氨酰胺（GGG）循环。然而，星形胶质细胞向神经末梢转运谷氨酰胺以及星形胶质细胞衍生的谷氨酰胺对神经递质 GABA 合成的贡献尚未得到明确的证明。通过基因敲除氨基酸转运蛋白溶质载体 38 成员 a1（Slc38a1）-其在 GABA 能神经元上丰富表达-并通过腹腔内注射放射性标记的乙酸（在星形胶质细胞中代谢为谷氨酰胺），我们表明 Slc38a1 介导星形胶质细胞衍生的谷氨酰胺进入 GABA 能神经元，用于 GABA 的合成。在脑切片中，我们证明了 Slc38a1 在 GABA 能神经末梢摄取谷氨酰胺以合成 GABA 方面的作用，这取决于需求和谷氨酰胺供应。因此，尽管存在其他途径，但我们的研究表明 Slc38a1 在新形成的 GABA 中的关键作用，与 GGG 循环的存在一致。
