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Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke

机译:减少过度的GABA介导的强直抑制作用可促进中风后的功能恢复

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摘要

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 shows heightened neuroplasticity, allowing sensorimotor functions to re-map from damaged areas. Thus, understanding the neuronal properties constraining this plasticity is important for the development of 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 GABA_A receptors and is caused by an impairment in GABA (γ-aminobutyric acid) transporter (GAT-3/GAT-4) function. To counteract the heightened inhibition, we administered in vivo a benzodiazepine inverse agonist specific for a5-subunit-containing extrasynaptic GABA_A receptors 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 GABA_A receptors responsible for tonic inhibition also proved beneficial for recovery after stroke, consistent with the therapeutic potential of diminishing extrasynaptic GABA_A receptor 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.
机译:中风是导致残疾的主要原因,但目前尚无药物疗法可促进康复。脑卒中损伤附近的大脑区域-梗死周围区域-对康复至关重要,因为它显示出增强的神经可塑性,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于开发新疗法很重要。在这里,我们显示了小鼠中风后,在梗塞周围区域的滋补神经元抑制作用增加了。这种增强的强直抑制作用是由突触外GABA_A受体介导的,并且是由GABA(γ-氨基丁酸)转运蛋白(GAT-3 / GAT-4)功能受损引起的。为了抵消增强的抑制作用,我们在卒中后延迟了体内对含a5亚基的突触外GABA_A受体具有特异性的苯二氮卓类反向激动剂。这种治疗可使运动功能尽早而持续地恢复。遗传上减少负责滋补抑制作用的含α5或δ亚基的GABA_A受体的数量也被证明对中风后的恢复有益,这与减少突触外GABA_A受体功能的治疗潜力相一致。在一起,我们的结果确定了新的药理学目标,并为促进卒中和其他可能的脑损伤后恢复的新策略提供了理论依据。

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  • 来源
    《Nature》 |2010年第7321期|p.305-309119121|共7页
  • 作者单位

    Department of Neurology, The David Geffen School of Medicine at UCLA, 635 Charles Young Drive South, Los Angeles, California 90095, USA Departments of Psychology and Anatomy and Structural Biology, University of Otago, PO Box 913, Dunedin 9013, New Zealand;

    rnDepartment of Neurology, The David Geffen School of Medicine at UCLA, 635 Charles Young Drive South, Los Angeles, California 90095, USA Interdepartmental PhD Program for Neuroscience, The David Geffen School of Medicine at UCLA, 635 Charles Young Drive South, Los Angeles, California 90095, USA;

    rnDepartment of Neurology, The David Geffen School of Medicine at UCLA, 635 Charles Young Drive South, Los Angeles, California 90095, USA;

    rnDepartment of Neurology, The David Geffen School of Medicine at UCLA, 635 Charles Young Drive South, Los Angeles, California 90095, USA Interdepartmental PhD Program for Neuroscience, The David Geffen School of Medicine at UCLA, 635 Charles Young Drive South, Los Angeles, California 90095, USA Department of Physiology, The David Geffen School of Medicine at UCLA, 635 Charles Young Drive South, Los Angeles, California 90095, USA;

    rnDepartment of Neurology, The David Geffen School of Medicine at UCLA, 635 Charles Young Drive South, Los Angeles, California 90095, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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