Original Article

Gene Therapy (2016) 23, 760–766; doi:10.1038/gt.2016.56; published online 4 August 2016

DREADDs suppress seizure-like activity in a mouse model of pharmacoresistant epileptic brain tissue

N Avaliani1, M Andersson1, A H Runegaard2, D Woldbye3 and M Kokaia1

  1. 1Epilepsy Centre, Experimental Epilepsy Group, Department of Clinical Sciences, Lund University Hospital, Lund, Sweden
  2. 2Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark
  3. 3Laboratory of Neural Plasticity, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark

Correspondence: Professor M Kokaia, Epilepsy Center, Experimental Epilepsy Group, Department of Clinical Sciences, Lund University Hospital, Solvegatan 17, BMC A11, Lund 22184, Sweden. E-mail: merab.kokaia@med.lu.se

Received 30 May 2016; Accepted 20 June 2016
Accepted article preview online 14 July 2016; Advance online publication 4 August 2016

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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.