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Chemogenetics: Beyond Lesions and Electrodes.

ABSTRACT: The field of chemogenetics has rapidly expanded over the last decade, and engineered receptors are currently utilized in the lab to better understand molecular interactions in the nervous system. We propose that chemogenetic receptors can be used for far more than investigational purposes. The potential benefit of adding chemogenetic neuromodulation to the current neurosurgical toolkit is substantial. There are several conditions currently treated surgically, electrically, and pharmacologically in clinic, and this review highlights how chemogenetic neuromodulation could improve patient outcomes over current neurosurgical techniques. We aim to emphasize the need to take these techniques from bench to bedside.

SUBMITTER: Poth KM

PROVIDER: S-EPMC8279839 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Chemogenetics: Beyond Lesions and Electrodes.

Poth Kelly M KM Texakalidis Pavlos P Boulis Nicholas M NM

Neurosurgery 20210701 2

The field of chemogenetics has rapidly expanded over the last decade, and engineered receptors are currently utilized in the lab to better understand molecular interactions in the nervous system. We propose that chemogenetic receptors can be used for far more than investigational purposes. The potential benefit of adding chemogenetic neuromodulation to the current neurosurgical toolkit is substantial. There are several conditions currently treated surgically, electrically, and pharmacologically ...[more]

PMID: 33913505

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Project description: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.

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Chemogenetics: Beyond Lesions and Electrodes.

Publications

Chemogenetics: Beyond Lesions and Electrodes.

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