Center for Neuroscience, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea.
Cell Rep. 2020 Jul 7;32(1):107861. doi: 10.1016/j.celrep.2020.107861.
Glucose hypometabolism in cortical structures after functional disconnection is frequently reported in patients with white matter diseases such as subcortical stroke. However, the molecular and cellular mechanisms have been poorly elucidated. Here we show, in an animal model of internal capsular infarct, that GABA-synthesizing reactive astrocytes in distant cortical areas cause glucose hypometabolism via tonic inhibition of neighboring neurons. We find that reversal of aberrant astrocytic GABA synthesis, by pharmacological inhibition and astrocyte-specific gene silencing of MAO-B, reverses the reduction in cortical glucose metabolism. Moreover, induction of aberrant astrocytic GABA synthesis by cortical injection of putrescine or adenovirus recapitulates cortical hypometabolism. Furthermore, MAO-B inhibition causes a remarkable recovery from post-stroke motor deficits when combined with a rehabilitation regimen. Collectively, our data indicate that cortical glucose hypometabolism in subcortical stroke is caused by aberrant astrocytic GABA and MAO-B inhibition and that attenuating cortical hypometabolism can be a therapeutic approach in subcortical stroke.
皮质结构的葡萄糖代谢低下在皮质下卒中等白质疾病患者中经常被报道。然而，其分子和细胞机制仍未被很好地阐明。在这里，我们在一个内囊梗死的动物模型中显示，在远处皮质区合成 GABA 的反应性星形胶质细胞通过对邻近神经元的紧张性抑制导致葡萄糖代谢低下。我们发现，通过药物抑制和 MAO-B 的星形胶质细胞特异性基因沉默来逆转异常星形胶质细胞 GABA 合成，可逆转皮质葡萄糖代谢的降低。此外，通过向皮质内注射腐胺或腺病毒诱导异常的星形胶质细胞 GABA 合成，可重现皮质代谢低下。此外，MAO-B 抑制与康复方案联合使用时可显著改善卒中后的运动障碍。总之，我们的数据表明，皮质下卒中引起的皮质葡萄糖代谢低下是由异常的星形胶质细胞 GABA 和 MAO-B 抑制引起的，并且减轻皮质代谢低下可能是皮质下卒中的一种治疗方法。
