Characterization of inhibitory GABA-A receptor activation during spreading depolarization in brain slice.
Characterization of inhibitory GABA-A receptor activation during spreading depolarization in brain slice.
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DOI：
10.1371/journal.pone.0110849
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Shuttleworth CW
中科院分区：
文献类型：
--
作者：
Aiba I;Shuttleworth CW
扩张性去极化（SD）是神经元和胶质细胞接近完全去极化的缓慢传播波。先前的研究报道了在SD过程中大量的GABA释放，但对GABA释放和受体激活如何被调节和影响传播的SD波前以及SD通过后的兴奋期的了解有限。本研究研究了KCl显微注射在成年小鼠急性海马切片中产生的GABA-A型受体（GABAAR）电流。自发gabaar介导的电流（sIPSCs）最初增强，随后在波前出现大的外向电流。sIPSC在SD后期被短暂抑制，导致sIPSC/sEPSC比值显著降低。在SD过程中产生的大外向电流被GABAAR拮抗剂gabazine消除，但通道增强剂/激动剂异丙酚未能增强电流，可能是由于天花板效应。SD期间记录的细胞外Cl -减少量被拮抗剂减少，但未被增强剂增加。结合GABAAR调节剂对SD繁殖速率的影响，这些结果证明了初始GABAAR激活的显著抑制作用，并表明细胞内Cl−负载不足以在SD繁殖过程中产生兴奋性GABAAR反应。这些结果为GABAAR拮抗剂的促进作用和GABAAR增强剂对SD繁殖缺乏抑制作用提供了机制解释。此外，GABA在SD后期的选择性抑制和GABAA调节剂对SD持续时间的影响不足表明GABA调制可能不是有效保护SD易损期神经元的方法。
Spreading depolarization (SD) is a slowly propagating wave of near complete depolarizations of neurons and glia. Previous studies have reported large GABA releases during SD, but there is limited understanding of how GABA release and receptor activation are regulated and influence the propagating SD wavefront, as well as an excitatory phase immediately following the passage of SD. The present study characterized GABA-A type receptor (GABAAR) currents during SD generated by KCl microinjection in acute hippocampal slices from adult mice. Spontaneous GABAAR-mediated currents (sIPSCs) were initially enhanced, and were followed by a large outward current at the wavefront. sIPSC were then transiently supressed during the late SD phase, resulting in a significant reduction of the sIPSC/sEPSC ratio. The large outward current generated during SD was eliminated by the GABAAR antagonist gabazine, but the channel potentiator/agonist propofol failed to potentiate the current, likely because of a ceiling effect. Extracellular Cl− decreases recorded during SD were reduced by the antagonist but were not increased by the potentiator. Together with effects of GABAAR modulators on SD propagation rate, these results demonstrate a significant inhibitory role of the initial GABAAR activation and suggest that intracellular Cl− loading is insufficient to generate excitatory GABAAR responses during SD propagation. These results provide a mechanistic explanation for facilitating effects of GABAAR antagonists, and the lack of inhibitory effect of GABAAR potentiators on SD propagation. In addition, selective suppression of GABA transmission in the late SD period and the lack of effect of GABAA modulators on the duration of SD suggests that GABA modulation may not be effective approach to protect neurons during the vulnerable phase of SD.
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