Novel hybrid action of GABA mediates inhibitory feedback in the mammalian retina
Novel hybrid action of GABA mediates inhibitory feedback in the mammalian retina
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DOI：
10.1371/journal.pbio.3000200
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发表时间：
2019-04-01
期刊：
影响因子：
9.8
通讯作者：
Barnes, Steven
中科院分区：
文献类型：
--
作者：
Grove, James C. R.;Hirano, Arlene A.;Barnes, Steven
从光感受器发送到二阶双极细胞的视觉信息流被横向相互作用的水平细胞拦截，这些水平细胞产生反馈以优化和提高信号传输的效率。在这个nonspiking网络的分级感光突触输出的调节机制仍然难以捉摸。在这里，我们用膜片钳记录来分析水平细胞控制突触间隙pH值以调节光感受器神经递质释放的新机制。首先，我们表明，哺乳动物的水平细胞响应自己的GABA的释放，这种autaptic行动的结果影响锥电压门控Ca 2+通道（Ca-V通道）门控通过pH值的变化。作为一个证明的原则，我们表明，化学遗传操纵水平细胞与外源阴离子通道表达模仿GABA介导的锥Ca-V通道抑制。GABA受体阴离子通道的激活可以通过Na+/H+交换器（NHE）质子的排出，使水平细胞去极化，增加裂隙酸度，从而抑制视锥细胞Ca-V通道。当水平细胞通过增加GABA受体（GABAR）介导的HCO 3-流出而充分超极化时，这种作用被有效地抵消，使裂隙碱化并解除对锥体Ca-V通道的抑制。这证明了GABA的混合作用如何平行地影响电压依赖性pH变化，这是一种调节突触输出的新机制。
The stream of visual information sent from photoreceptors to second-order bipolar cells is intercepted by laterally interacting horizontal cells that generate feedback to optimize and improve the efficiency of signal transmission. The mechanisms underlying the regulation of graded photoreceptor synaptic output in this nonspiking network have remained elusive. Here, we analyze with patch clamp recording the novel mechanisms by which horizontal cells control pH in the synaptic cleft to modulate photoreceptor neurotransmitter release. First, we show that mammalian horizontal cells respond to their own GABA release and that the results of this autaptic action affect cone voltage-gated Ca2+ channel (Ca-V channel) gating through changes in pH. As a proof-of-principle, we demonstrate that chemogenetic manipulation of horizontal cells with exogenous anion channel expression mimics GABA-mediated cone Ca-V channel inhibition. Activation of these GABA receptor anion channels can depolarize horizontal cells and increase cleft acidity via Na+/H+ exchanger (NHE) proton extrusion, which results in inhibition of cone Ca-V channels. This action is effectively counteracted when horizontal cells are sufficiently hyperpolarized by increased GABA receptor (GABAR)-mediated HCO3- efflux, alkalinizing the cleft and disinhibiting cone Ca-V channels. This demonstrates how hybrid actions of GABA operate in parallel to effect voltage-dependent pH changes, a novel mechanism for regulating synaptic output.