Environmental enrichment implies GAT-1 as a potential therapeutic target for stroke recovery.
Environmental enrichment implies GAT-1 as a potential therapeutic target for stroke recovery.
复制标题
环境富集意味着 GAT-1 作为中风恢复的潜在治疗靶点
作者：
Lin Y;Yao M;Wu H;Wu F;Cao S;Ni H;Dong J;Yang D;Sun Y;Kou X;Li J;Xiao H;Chang L;Wu J;Liu Y;Luo C;Zhu D
理由：卒中是全球成人残疾的主要原因，但没有药物在修复阶段提供功能恢复。越来越多的证据表明，丰富的环境（EE）通过增强网络兴奋性促进中风恢复。然而，在临床环境中使用EE的复杂性限制了其翻译。研究方法：我们使用多方面的方法结合电生理学，化学遗传学，光遗传学和floxed小鼠在小鼠光血栓形成中风模型，以揭示EE介导的中风恢复的关键目标。结果如下：EE减少紧张性γ-氨基丁酸（GABA）抑制，促进梗死周围皮层的阶段性GABA抑制，从而促进网络兴奋性和中风恢复。这些有益的效果依赖于GAT-1，GABA转运蛋白调节紧张性和阶段性GABA信号，EE积极调节GAT-1的表达，运输和功能。此外，GAT-1是必要的EE诱导的网络可塑性，包括结构神经可塑性，输入突触在梗死周围皮层的加强，输出突触在皮质脊髓束的加强，和发芽的未受伤的皮质脊髓轴突穿过中线到失神经脊髓的领土，从中风的功能恢复。此外，通过GAT-1的过表达恢复梗死周围皮层中的GAT-1功能显示出与EE暴露类似的对中风恢复的有益作用。结论：GAT-1是EE对网络兴奋性和随后的中风恢复的作用的关键分子底物，并且可以在修复阶段作为中风治疗的新的治疗靶点。
Rationale: Stroke is a leading cause of adult disability worldwide, but no drug provides functional recovery during the repair phase. Accumulating evidence demonstrates that environmental enrichment (EE) promotes stroke recovery by enhancing network excitability. However, the complexities of utilizing EE in a clinical setting limit its translation. Methods: We used multifaceted approaches combining electrophysiology, chemogenetics, optogenetics, and floxed mice in a mouse photothrombotic stroke model to reveal the key target of EE-mediated stroke recovery. Results: EE reduced tonic gamma-aminobutyric acid (GABA) inhibition and facilitated phasic GABA inhibition in the peri-infarct cortex, thereby promoting network excitability and stroke recovery. These beneficial effects depended on GAT-1, a GABA transporter regulating both tonic and phasic GABA signaling, as EE positively regulated GAT-1 expression, trafficking, and function. Furthermore, GAT-1 was necessary for EE-induced network plasticity, including structural neuroplasticity, input synaptic strengthening in the peri-infarct cortex, output synaptic strengthening in the corticospinal tract, and sprouting of uninjured corticospinal axons across the midline into the territory of denervated spinal cord, and functional recovery from stroke. Moreover, restoration of GAT-1 function in the peri-infarct cortex by its overexpression showed similar beneficial effects on stroke recovery as EE exposure. Conclusion: GAT-1 is a key molecular substrate of the effects of EE on network excitability and consequent stroke recovery and can serve as a novel therapeutic target for stroke treatment during the repair phase.