S-Nitrosylation of Dexras1 Controls Post-Stroke Recovery via Regulation of Neuronal Excitability and Dendritic Remodeling

Stroke is a major public health concern leading to high rates of death and disability worldwide, unfortunately with no effective treatment available for stroke recovery during the repair phase.

Thus, inhibition of SNO-Dexras1 positively regulates post-stroke functional recovery via enhanced neuronal excitability and dendritic remodeling. Our results identify that SNO-Dexras1 may serve as a novel target for promoting motor functional restoration from stroke in the delayed phase, shedding light on stroke treatment.

Photothrombotic stroke was induced in mice. Adeno-associated viruses (AAV) were microinjected into the peri-infarct cortex immediately after photothrombotic stroke. Grid-walking task and cylinder task were used to assess motor function. Western blotting, Golgi staining, and electrophysiology recordings were performed to uncover the mechanisms.

The ternary complex of neuronal nitric oxide synthase (nNOS), carboxy-terminal PDZ ligand of nNOS (CAPON) and dexamethasone-induced ras protein 1 (Dexras1) is structurally beneficial for S-nitrosylation of Dexras1 (SNO-Dexras1). In our previous study, uncoupling nNOS-CAPON interaction by Tat-CAPON-12C promoted functional recovery after stroke. Here, we show that ischemia elevated the levels of nNOS-Dexras1 complex and SNO-Dexras1 in the peri-infarct cortex in the days 4-10 after stroke induction, and as excepted, Tat-CAPON-12C, a peptide disrupting nNOS-CAPON interaction, significantly reversed these changes. The above information implies that repressed SNO-Dexras1 may mediate functional-promoting effects of Tat-CAPON-12C and SNO-Dexras1 could be the vital molecular substrate for post-stroke functional recovery in the repair phage. Inhibiting the ischemia-induced SNO-Dexras1 by AAV vector-mediated knockdown of Dexras1 or over-expression of dominant negative Dexras1 (Dexras1-C11S) produced sustained recovery of motor function from stroke. In contrast, up-regulation of SNO-Dexras1 by over-expressing Dexras1 worsened stroke outcome. Using electrophysiology recordings, we also observed that silence of Dexras1 in the peri-infarct cortex increased the spike number and the miniature excitatory postsynaptic currents (mEPSCs) frequency, suggesting enhancement of neuronal excitability. In addition, silence of Dexras1 increased dendritic complexity in cultured neuron and more importantly enhanced dendritic spine density in the peri-infarct cortex, implying dendritic remodeling.