title: DREADDs suppress seizure-like activity in a mouse model of pharmacoresistant epileptic brain tissue.
abstract: Epilepsy is a neurological disorder with a prevalence of ≈1% of general population. Available antiepileptic drugs (AEDs) have multiple side effects and are ineffective in 30% of patients. Therefore, development of effective treatment strategies is highly needed, requiring drug-screening models that are relevant and reliable. We investigated novel chemogenetic approach, using DREADDs (designer receptors exclusively activated by designer drugs) as possible inhibitor of epileptiform activity in organotypic hippocampal slice cultures (OHSCs). The OHSCs are characterized by increased overall excitability and closely resemble features of human epileptic tissue. Studies suggest that chemically induced epileptiform activity in rat OHSCs is pharmacoresistant to most of AEDs. However, high-frequency electric stimulus train-induced bursting (STIB) in OHSCs is responsive to carbamazepine and phenytoin. We investigated whether inhibitory DREADD, hM4Di, would be effective in suppressing STIB in OHSC. hM4Di is a mutated muscarinic receptor selectively activated by otherwise inert clozapine-N-oxide, which leads to hyperpolarization in neurons. We demonstrated that this hyperpolarization effectively suppresses STIB in mouse OHSCs. As we also found that STIB in mouse OHSCs is resistant to common AED, valproic acid, collectively our findings suggest that DREADD-based strategy may be effective in suppressing epileptiform activity in a pharamcoresitant epileptic brain tissue.
authors.affiliation: Epilepsy Centre, Experimental Epilepsy Group, Department of Clinical Sciences, Lund University Hospital, Lund, Sweden.
authors.forename: N
authors.identifier: 0000-0002-2986-1520
authors.initials: N
authors.lastname: Avaliani
authors.affiliation: Epilepsy Centre, Experimental Epilepsy Group, Department of Clinical Sciences, Lund University Hospital, Lund, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Andersson
authors.affiliation: Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: A H
authors.initials: AH
authors.lastname: Runegaard
authors.affiliation: Laboratory of Neural Plasticity, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: D
authors.initials: D
authors.lastname: Woldbye
authors.affiliation: Epilepsy Centre, Experimental Epilepsy Group, Department of Clinical Sciences, Lund University Hospital, Lund, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Kokaia
mesh_terms: D000200:Action Potentials; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology*; D000069279:Drug Resistant Epilepsy / Q000235:genetics* / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism*
chemical_list: D000927:Anticonvulsants; D018721:Muscarinic Agonists; D011976:Receptors, Muscarinic; D003024:Clozapine