Excessive astrocytic GABA causes cortical hypometabolism and impedes functional recovery following subcortical stroke
- Excessive astrocytic GABA causes cortical hypometabolism and impedes functional recovery following subcortical stroke
- 오수진; 박기덕; 남민호; 최지원; 조종욱; 권대혁; 박지영; 우준성; 이정무; 이상원; 고해영; 원우진; 김라경; 송한림; 박은경; 정혜진; 김형석; 이민철; 윤미진; 이창준; 김형일
- Issue Date
- Cell Reports
- 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.
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