Glial modulation for functional recovery in chronic stroke model

Abstract

Stroke is a leading cause of death and disability. Various neuromodulatory therapies combining with intensive intervention for post-stroke recovery have been developed. Recent work demonstrated that glia contributes to synaptic plasticity and functional recovery in the several days to weeks after brain ischemia. Glia provide benefit for neuroprotection, by limiting lesion extension via anti-excitotoxicity effects and releasing neurotrophines. In addition, they contribute to neurogenesis, synaptogenesis and axonal remodeling. Thus, glial modulation has a huge potential for promoting functional recovery after stroke. Existing stimulation techniques stimulates unselective cells near the stimulated areas and it made difficult to investigate contribution of astrocyte after stroke. But now, recent advance technique made possible to modulate cell specific stimulation. In this study, we applied optogenetics to investigate a feasibility of glial modulation for post-stroke recovery in chronic subcortical stroke model. All rats underwent underwent a photothrombotic stroke in the posterior limb of the internal capsule (PLIC). For glial modulation, rats were transduced with Lenti-ChR2-GFAP and Lenti-optoSTIM1-GFAP in the ipsilesional sensory-parietal cortex. Animals received optogenetic stimulation with behavioral evaluations. In addition, longitudinal 18F-FDG microPET was used to investigate changes in regional brain metabolism depending on effects of glial stimulation. Moreover, Ca2+ imaging was performed to observe changes in intracellular calcium level in the optoSTIM1-expressing astrocyte. Furthermore, c-Fos, activity-dependent immunostaining was used to validate existence of neuronal excitability via glial modulation. Behavioral results showed that modulation of astrocyte was beneficial for functional recovery after stroke. In the FDG-microPET, the reduction of cortical diaschisis was observed, and it strongly correlated with motor performances. In addition, an increase in metabolic rates were observed in the ipsilesional motor and sensory cortex after optogenetic stimulation. These activations may occur due to the elevation of intracellular calcium level in astrocyte which can induce release of gliotransmitter, and it is possible to modulate neuronal activity. Presence of c-Fos positive cells was founded in neuron adjacent to optoSTIM1-expressing glial cells after optogenetic stimulation, which might be evidence for glial-neuronal interaction. Accumulating evidence have demonstrated that glia bidirectionally interact with neurons through glio-transmission via tripartite synapse. As a result, optogenetic glial stimulation is possible to modulate synaptic function and can promote neuroplasticity. Therefore, developing new drug for targeting glial cell could have huge potential for stroke treatment.