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Chemogenetics-mediated acute inhibition of excitatory neuronal activity improves stroke outcome.

Publication ,  Journal Article
Wang, Y-C; Galeffi, F; Wang, W; Li, X; Lu, L; Sheng, H; Hoffmann, U; Turner, DA; Yang, W
Published in: Exp Neurol
April 2020

BACKGROUND AND PURPOSE: Ischemic 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. METHODS: We 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. RESULTS: Detailed 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. CONCLUSIONS: Our 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.

Duke Scholars

Published In

Exp Neurol

DOI

EISSN

1090-2430

Publication Date

April 2020

Volume

326

Start / End Page

113206

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Synapses
  • Stroke
  • Reperfusion Injury
  • Psychomotor Performance
  • Prosencephalon
  • Neuroprotection
  • Neurology & Neurosurgery
  • Motor Cortex
  • Mice, Transgenic
 

Citation

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ICMJE
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Wang, Y.-C., Galeffi, F., Wang, W., Li, X., Lu, L., Sheng, H., … Yang, W. (2020). Chemogenetics-mediated acute inhibition of excitatory neuronal activity improves stroke outcome. Exp Neurol, 326, 113206. https://doi.org/10.1016/j.expneurol.2020.113206
Wang, Ya-Chao, Francesca Galeffi, Wei Wang, Xuan Li, Liping Lu, Huaxin Sheng, Ulrike Hoffmann, Dennis A. Turner, and Wei Yang. “Chemogenetics-mediated acute inhibition of excitatory neuronal activity improves stroke outcome.Exp Neurol 326 (April 2020): 113206. https://doi.org/10.1016/j.expneurol.2020.113206.
Wang Y-C, Galeffi F, Wang W, Li X, Lu L, Sheng H, et al. Chemogenetics-mediated acute inhibition of excitatory neuronal activity improves stroke outcome. Exp Neurol. 2020 Apr;326:113206.
Wang, Ya-Chao, et al. “Chemogenetics-mediated acute inhibition of excitatory neuronal activity improves stroke outcome.Exp Neurol, vol. 326, Apr. 2020, p. 113206. Pubmed, doi:10.1016/j.expneurol.2020.113206.
Wang Y-C, Galeffi F, Wang W, Li X, Lu L, Sheng H, Hoffmann U, Turner DA, Yang W. Chemogenetics-mediated acute inhibition of excitatory neuronal activity improves stroke outcome. Exp Neurol. 2020 Apr;326:113206.
Journal cover image

Published In

Exp Neurol

DOI

EISSN

1090-2430

Publication Date

April 2020

Volume

326

Start / End Page

113206

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Synapses
  • Stroke
  • Reperfusion Injury
  • Psychomotor Performance
  • Prosencephalon
  • Neuroprotection
  • Neurology & Neurosurgery
  • Motor Cortex
  • Mice, Transgenic