Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke.
Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke.
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中风是导致残疾的主要原因；但目前还没有药物治疗可以促进康复。与中风损伤相邻的大脑区域，即梗死周围区，对康复至关重要，因为它表现出高度的神经可塑性，允许感觉运动功能从受损区域重新映射。因此，了解限制这种可塑性的神经元特性对开发新的治疗方法很重要。在这里，我们表明，在小鼠中风后，强直性神经元抑制在梗死周围区增加。这种增强的强直抑制是由突触外GABAA受体（GABAARs）介导的，是由GABA转运体（GAT-3/4）功能受损引起的。为了抵消这种增强的抑制作用，我们在脑卒中后延迟给药一种苯二氮卓类逆激动剂，用于含有α5亚基的突触外GABAARs。这种治疗产生了早期和持续的运动功能恢复。从基因上降低α5或δ亚基GABAAR的数量也被证明对中风后的恢复有益，这与减少突触外GABAAR功能的治疗潜力是一致的。总之，我们的研究结果确定了新的药理学靶点，并为促进中风和其他脑损伤后恢复的新策略提供了基本原理。
Stroke is a leading cause of disability; but no pharmacological therapy is currently available for promoting recovery. The brain region adjacent to stroke damage, the peri-infarct zone, is critical for rehabilitation, as it exhibits heightened neuroplasticity, allowing sensorimotor functions to re-map from damaged areas. Thus, understanding the neuronal properties constraining this plasticity is important to developing new treatments. Here we show that after a stroke in mice, tonic neuronal inhibition is increased in the peri-infarct zone. This increased tonic inhibition is mediated by extrasynaptic GABAA receptors (GABAARs) and is caused by an impairment in GABA transporter (GAT-3/4) function. To counteract the heightened inhibition, we administered in vivo a benzodiazepine inverse agonist specific for the α5-subunit-containing extrasynaptic GABAARs at a delay after stroke. This treatment produced an early and sustained recovery of motor function. Genetically lowering the number of α5 or δ-subunit-containing GABAARs responsible for tonic inhibition also proved beneficial for post-stroke recovery, consistent with the therapeutic potential of diminishing extrasynaptic GABAAR function. Together, our results identify new pharmacological targets and provide the rationale for a novel strategy to promote recovery after stroke and possibly other brain injuries.
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