• 027049

    Optogenetic stimulation reduces neuronal nitric oxide synthase expression after stroke


    Gary Steinberg, Michelle Cheng, Arjun Pendharkar


    Introduction: Post-stroke optogenetic stimulation has been shown to enhance neurovascular coupling and functional recovery. Neuronal nitric oxide synthase (nNOS) has been implicated as a key regulator of the neurovascular response in acute stroke but its role in subacute recovery remains unclear.

    Objective: Here we investigate the expression of nNOS in stroke mice undergoing optogenetic stimulation of the contralesional lateral cerebellar nucleus (cLCN). We also examine the effects of nNOS inhibition on functional recovery using a pharmacological inhibitor targeting nNOS.

    Methods: Transgenic mice harboring channelrhodopsin were implanted with optical cannulas in the cLCN. Transient middle cerebral artery occlusion was induced and optogenetic stimulation was delivered on post-stroke days 5-14. NOS isoform mRNA and protein levels were assayed at day 15. In a separate experiment, a systemic nNOS inhibitor (ARL 17477) was administered on post-stroke day 5-14. Behavioral testing was again conducted to evaluate functional recovery.

    Results: Optogenetically stimulated stroke mice demonstrated significant improvement on the horizontal rotating beam task at post-stroke day 10 and 14. nNOS mRNA and protein expression was significantly and selectively decreased in the contralesional primary motor cortex (cM1) of cLCN stimulated mice. The reduced nNOS expression in cM1 was negatively correlated with improved recovery. nNOS inhibitor (ARL 17477)-treated stroke mice exhibited a significant functional improvement in speed at post-stroke day 10, when compared to stroke mice receiving vehicle (saline) only. Optogenetic stimulation of cLCN and systemic nNOS inhibition both produce functional benefits after stroke.

    Conclusions: Our results suggest that nNOS may play a maladaptive role in post-stroke recovery.

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