Regulation of cortical microcircuits by unitary GABA-mediated volume transmission.
Regulation of cortical microcircuits by unitary GABA-mediated volume transmission.
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γ -氨基丁酸（GABA）主要由大脑皮层的局部中间神经元释放到靶细胞的特定亚细胞区域。这表明，在皮层网络中，GABA的区隔化、突触特异性作用是相位抑制所必需的。然而，在突触间隙释放的GABA扩散到突触后密度外的受体，从而强直激活突触外GABAA和GABAB受体，其中包括对低浓度GABA特别敏感的两种受体家族亚型。GABA的突触和突触外作用与大脑神经元使用突触（或线路）传递和非突触（或体积）传递进行通信的观点一致。然而，再摄取机制限制了突触外GABA能效应的空间范围，有人提出，需要几个突触前中间神经元的协同作用或单个细胞的持续放电或释放位点密度的增加，才能达到足以激活突触外受体的环境GABA水平。在这里，我们发现单个神经胶质样细胞释放的GABA足以在轴突云内进行体积传递，因此神经胶质样细胞不需要突触在绝大多数附近神经元中产生抑制反应。神经胶质细胞抑制作用于突触前终末的其他神经元之间的连接，这些神经元在大脑皮层中根本不接受突触，而且，到达突触外，含有GABAA （gabaδ）受体的δ亚基负责强直抑制。我们发现gabaδ受体在皮层中间神经元中优先定位于神经胶质细胞。神经类固醇是GABAAδ受体的调节剂，可以改变神经胶质细胞之间的单一GABAAδ能效应。与其他中间神经元形成的特异性突触相反，神经类固醇敏感神经胶质样细胞的输出代表了gaba能系统中空间非特异性的最终形式，导致持久的网络超极化，并结合局部电路中广泛抑制通信。
Gamma-aminobutyric acid (GABA) is predominantly released by local interneurons in the cerebral cortex to particular subcellular domains of the target cells. This suggests that compartmentalized, synapse specific action of GABA is required in cortical networks for phasic inhibition. However, GABA released at the synaptic cleft diffuses to receptors outside the postsynaptic density and thus tonically activates extrasynaptic GABAA and GABAB receptors, which include subtypes of both receptor families especially sensitive to low concentrations of GABA. The synaptic and extrasynaptic action of GABA is in line with idea that neurons of the brain use synaptic (or wiring) transmission and nonsynaptic (or volume) transmission for communication. However, reuptake mechanisms restrict the spatial extent of extrasynaptic GABAergic effects and it was proposed that concerted action of several presynaptic interneurons or sustained firing of individual cells or increased release site density is required to reach ambient GABA levels sufficient to activate extrasynaptic receptors. Here we show that individual neurogliaform cells release GABA sufficient for volume transmission within the axonal cloud and thus neurogliaform cells do not require synapses to produce inhibitory responses in the overwhelming majority of nearby neurons. Neurogliaform cells suppress connections between other neurons acting on presynaptic terminals which do not receive synapses at all in the cerebral cortex and, moreover, reach extrasynaptic, δ subunit containing GABAA (GABAAδ) receptors responsible for tonic inhibition. We reveal that GABAAδ receptors are localized to neurogliaform cells preferentially among cortical interneurons. Neurosteroids, which are modulators of GABAAδ receptors, alter unitary GABAergic effects between neurogliaform cells. In contrast to the specifically placed synapses formed by other interneurons, the output of neurosteroid sensitive neurogliaform cells represents the ultimate form of spatial unspecificity in GABAergic systems leading to long lasting network hyperpolarization combined with widespread suppression of communication in the local circuit.
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