Ketone bodies promote stroke recovery via GAT-1-dependent cortical network remodeling

Stroke is a leading cause of adult disability worldwide, and better drugs are needed to promote functional recovery after stroke. Growing evidence suggests the critical role of network excitability during the repair phase for stroke recovery. Here, we show that b-hydroxybutyrate (b-HB), an essential ketone body (KB) component, is positively correlated with improved outcomes in patients with stroke and promotes functional recovery in rodents with stroke during the repair phase. These beneficial effects of b-HB depend on HDAC2/HDAC3-GABA transporter 1 (GAT-1) signaling-mediated enhancement of excitability and phasic GABA inhibition in the peri-infarct cortex and structural and functional plasticity in the ipsilat-eral cortex, the contralateral cortex, and the corticospinal tract. Together with available clinical ap-proaches to elevate KB levels, our results offer a clinically translatable means to promote stroke recovery. Furthermore, GAT-1 can serve as a pharmacological target for developing drugs to promote functional recovery after stroke.

Automated summary

Stroke is a major cause of adult disability globally and better drugs are required for functional recovery after stroke. This study demonstrates the positive correlation between b-hydroxybutyrate (b-HB) and improved outcomes in stroke patients, as well as the promotion of functional recovery in rodents during the repair phase. The beneficial effects of b-HB rely on the enhancement of excitability and phasic GABA inhibition, as well as structural and functional plasticity mediated by HDAC2/HDAC3-GABA transporter 1 (GAT-1) signaling. These findings offer a clinically translatable approach for stroke recovery and identify GAT-1 as a potential pharmacological target.