Chemogenetics-mediated acute inhibition of excitatory neuronal activity improves stroke outcome.
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Background and purposeIschemic stroke significantly perturbs neuronal homeostasis leading to a cascade of pathologic events causing brain damage. In this study, we assessed acute stroke outcome after chemogenetic inhibition of forebrain excitatory neuronal activity.
MethodsWe generated hM4Di-TG transgenic mice expressing the inhibitory hM4Di, a Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic receptor, in forebrain excitatory neurons. Clozapine-N-oxide (CNO) was used to activate hM4Di DREADD. Ischemic stroke was induced by transient occlusion of the middle cerebral artery. Neurologic function and infarct volumes were evaluated. Excitatory neuronal suppression in the hM4Di-TG mouse forebrain was assessed electrophysiologically in vitro and in vivo, based on evoked synaptic responses, and in vivo based on occurrence of potassium-induced cortical spreading depolarizations.
ResultsDetailed characterization of hM4Di-TG mice confirmed that evoked synaptic responses in both in vitro hippocampal slices and in vivo motor cortex were significantly reduced after CNO-mediated activation of the inhibitory hM4Di DREADD. Further, CNO treatment had no obvious effects on physiology and motor function in either control or hM4Di-TG mice. Importantly, hM4Di-TG mice treated with CNO at either 10 min before ischemia or 30 min after reperfusion exhibited significantly improved neurologic function and smaller infarct volumes compared to CNO-treated control mice. Mechanistically, we showed that potassium-induced cortical spreading depression episodes were inhibited, including frequency and duration of DC shift, in CNO-treated hM4Di-TG mice.
ConclusionsOur data demonstrate that acute inhibition of a subset of excitatory neurons after ischemic stroke can prevent brain injury and improve functional outcome. This study, together with the previous work in optogenetic neuronal modulation during the chronic phase of stroke, supports the notion that targeting neuronal activity is a promising strategy in stroke therapy.
Published Version (Please cite this version)
Wang, Ya-Chao, Francesca Galeffi, Wei Wang, Xuan Li, Liping Lu, Huaxin Sheng, Ulrike Hoffmann, Dennis A Turner, et al. (2020). Chemogenetics-mediated acute inhibition of excitatory neuronal activity improves stroke outcome. Experimental neurology, 326. p. 113206. 10.1016/j.expneurol.2020.113206 Retrieved from https://hdl.handle.net/10161/23241.
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We have successfully developed various rodent models of brain and spinal cord injuries in our lab, such as focal cerebral ischemia, global cerebral ischemia, head trauma, subarachnoid hemorrhage, intracerebral hemorrhage, spinal cord ischemia and compression injury. We also established cardiac arrest and hemorrhagic shock models for studying multiple organ dysfunction. Our current studies focus on two projects. One is to examine the efficacy of catalytic antioxidant in treating cerebral ischemia and the other is to examine the efficacy of post-conditioning on outcome of subarachnoid hemorrhage induced cognitive dysfunction.
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