Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target.
Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target.
复制标题
DOI：
10.1093/brain/awv360
复制
发表时间：
2016-02
期刊：
影响因子：
--
通讯作者：
Steinberg GK
中科院分区：
文献类型：
--
作者：
Hiu T;Farzampour Z;Paz JT;Wang EH;Badgely C;Olson A;Micheva KD;Wang G;Lemmens R;Tran KV;Nishiyama Y;Liang X;Hamilton SA;O'Rourke N;Smith SJ;Huguenard JR;Bliss TM;Steinberg GK
虽然强直性GABA似乎抑制脑卒中后的修复，但相（突触）GABA信号的作用尚不清楚。Hiu等人揭示了修复阶段阶段性GABA信号的增加，增强了小鼠的可塑性相关恢复。唑吡坦增加相信号可以改善行为恢复，提示治疗潜力。虽然强直性GABA似乎抑制脑卒中后的修复，但相（突触）GABA信号的作用尚不清楚。Hiu等人揭示了修复阶段阶段性GABA信号的增加，增强了小鼠的可塑性相关恢复。唑吡坦增加相信号可以改善行为恢复，提示治疗潜力。缺血性中风是严重长期残疾的主要原因，但缺乏促进修复阶段恢复的药物治疗。中风的修复阶段发生在中风发作后几天到几个月，涉及到梗死周围区域的大脑重新定位和可塑性。阐明促进这种可塑性的机制对于开发具有广泛治疗窗口的新疗法至关重要。据报道，在修复阶段抑制强直（突触外）GABA信号传导可以增强小鼠的功能恢复，这表明GABA在调节大脑修复中起重要作用。虽然强直性GABA似乎抑制脑卒中后的修复，但对修复阶段相（突触）GABA的作用知之甚少。我们观察到小鼠在5层梗死周围皮层内突触后相位GABA信号的增加；我们发现，通过阵列断层扫描检测到含有α1受体亚基的gaba能突触数量增加，锥体神经元中自发和微型抑制性突触后电流的有效性随之增加。此外，我们证明，在修复阶段，使用唑吡坦（一种美国食品和药物管理局（FDA）批准的GABA阳性变构调节剂）增强相GABA信号可以改善行为恢复。这些数据确定了增强相GABA信号作为一种新的治疗策略，表明唑吡坦有可能改善恢复，并强调了区分强直性和相性GABA信号在卒中恢复中的作用的必要性。
While tonic GABA appears to suppress brain repair after stroke, the effects of phasic (synaptic) GABA signalling are unclear. Hiu et al. reveal an increase in phasic GABA signalling during the repair phase that enhances plasticity-related recovery in mice. Increasing phasic signalling with zolpidem improves behavioural recovery, suggesting therapeutic potential. While tonic GABA appears to suppress brain repair after stroke, the effects of phasic (synaptic) GABA signalling are unclear. Hiu et al. reveal an increase in phasic GABA signalling during the repair phase that enhances plasticity-related recovery in mice. Increasing phasic signalling with zolpidem improves behavioural recovery, suggesting therapeutic potential. Ischaemic stroke is the leading cause of severe long-term disability yet lacks drug therapies that promote the repair phase of recovery. This repair phase of stroke occurs days to months after stroke onset and involves brain remapping and plasticity within the peri-infarct zone. Elucidating mechanisms that promote this plasticity is critical for the development of new therapeutics with a broad treatment window. Inhibiting tonic (extrasynaptic) GABA signalling during the repair phase was reported to enhance functional recovery in mice suggesting that GABA plays an important function in modulating brain repair. While tonic GABA appears to suppress brain repair after stroke, less is known about the role of phasic (synaptic) GABA during the repair phase. We observed an increase in postsynaptic phasic GABA signalling in mice within the peri-infarct cortex specific to layer 5; we found increased numbers of α1 receptor subunit-containing GABAergic synapses detected using array tomography, and an associated increased efficacy of spontaneous and miniature inhibitory postsynaptic currents in pyramidal neurons. Furthermore, we demonstrate that enhancing phasic GABA signalling using zolpidem, a Food and Drug Administration (FDA)-approved GABA-positive allosteric modulator, during the repair phase improved behavioural recovery. These data identify potentiation of phasic GABA signalling as a novel therapeutic strategy, indicate zolpidem’s potential to improve recovery, and underscore the necessity to distinguish the role of tonic and phasic GABA signalling in stroke recovery.