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

Gene Therapy volume 23, pages 760–766 (2016)Cite this article

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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.

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Acknowledgements

This work was supported by grants from (to MK): Swedish Research Council (2012-2258) and EPITARGET: FP7-HEALTH project (602102). We thank A Nøstdal for help with Figure 5 and proofreading the manuscript.

Author contributions

NA designed and performed research, analysed data and wrote the paper; MA designed research; AHR and DW designed research and provided material; MK designed research, wrote the paper and provided funding.

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Authors and Affiliations

  1. Department of Clinical Sciences, Epilepsy Centre, Experimental Epilepsy Group, Lund University Hospital, Lund, Sweden

    N Avaliani, M Andersson & M Kokaia

  2. Department of Neuroscience and Pharmacology, Molecular Neuropharmacology and Genetics Laboratory, University of Copenhagen, Copenhagen, Denmark

    A H Runegaard

  3. Department of Neuroscience and Pharmacology, Laboratory of Neural Plasticity, University of Copenhagen, Copenhagen, Denmark

    D Woldbye

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  1. N Avaliani
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Correspondence to M Kokaia.

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Avaliani, N., Andersson, M., Runegaard, A. et al. DREADDs suppress seizure-like activity in a mouse model of pharmacoresistant epileptic brain tissue. Gene Ther 23, 760–766 (2016). https://doi.org/10.1038/gt.2016.56

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