Chemogenetics: Beyond Lesions and Electrodes.
Ontology highlight
ABSTRACT:
SUBMITTER: Poth KM
PROVIDER: S-EPMC8279839 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chemogenetics enables noninvasive chemical control over cell populations in behaving animals. However, existing small-molecule agonists show insufficient potency or selectivity. There is also a need for chemogenetic systems compatible with both research and human therapeutic applications. We developed a new ion channel-based platform for cell activation and silencing that is controlled by low doses of the smoking cessation drug varenicline. We then synthesized subnanomolar-potency agonists, called uPSEMs, with high selectivity for the chemogenetic receptors. uPSEMs and their receptors were characterized in brains of mice and a rhesus monkey by in vivo electrophysiology, calcium imaging, positron emission tomography, behavioral efficacy testing, and receptor counterscreening. This platform of receptors and selective ultrapotent agonists enables potential research and clinical applications of chemogenetics.
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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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Project description:G. sulfurreducens (ATCC #51573) was obtained from the laboratory culture collection of Dr. Derek Lovley. Cells were grown under strict anaerobic conditions at 23 �Â�°C in batch culture. Both control and experimental populations were grown with 10mM acetate as the electron donor while Fe(III) as 55 mM ferric citrate served as the electron acceptor for the control populations and graphite anodes as the electron acceptor for the experimental populations. Controls populations were harvested at a concentration of 30 mM Fe(II). Fuel cell power output was monitored by measuring the voltage across a known resistance in the fuel cell and experimental populations were harvested when current production reached a steady state of 0.6 milliamperes. Cells were harvested at log phase by centrifugation at 4 �Â�°C and the cell pellet was flash-frozen in liquid nitrogen and then stored at -80 �Â�°C prior to RNA extraction. Three cultures of control and experimental populations were collected. Each culture vessel was harvested and extracted for total RNA separately to produce three biological replicates for this experiment. Additional information regarding the fuel cell experimental set up and culture conditions for this experiment can be found in both the current reference and the following reference: Bond DR and Lovley DR. Electricity production by Geobacter sulfurreducens attached to electrodes. 2003. Applied and Environmental Microbiology 69: 1548-1555.
2006-01-26 | E-TIGR-83 | biostudies-arrayexpress
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