Long-term chemogenetic suppression of seizures in a multifocal rat model of temporal lobe epilepsy
Marie-Gabrielle Goossens
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Search for more papers by this authorPaul Boon
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Search for more papers by this authorWytse Wadman
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Search for more papers by this authorChris Van den Haute
Laboratory for Neurobiology and Gene Therapy, Center for Molecular Medicine and Leuven Brain Institute, KU Leuven, Leuven, Belgium
Leuven Viral Vector Core, Center for Molecular Medicine, KU Leuven, Leuven, Belgium
Search for more papers by this authorVeerle Baekelandt
Laboratory for Neurobiology and Gene Therapy, Center for Molecular Medicine and Leuven Brain Institute, KU Leuven, Leuven, Belgium
Search for more papers by this authorAlain G. Verstraete
Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium
Search for more papers by this authorKristl Vonck
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Search for more papers by this authorLars E. Larsen
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Search for more papers by this authorMathieu Sprengers
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Search for more papers by this authorEvelien Carrette
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Search for more papers by this authorJana Desloovere
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Search for more papers by this authorAlfred Meurs
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Search for more papers by this authorJean Delbeke
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Search for more papers by this authorChristian Vanhove
IBiTech, Department of Electronics and Information Systems, Ghent University, Ghent, Belgium
Search for more papers by this authorCorresponding Author
Robrecht Raedt
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Correspondence
Robrecht Raedt, 4BRAIN, Department of Head and Skin, Ghent University, Corneel Heymanslaan 10, Ghent, Belgium.
Email: [email protected].
Search for more papers by this authorMarie-Gabrielle Goossens
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Search for more papers by this authorPaul Boon
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Search for more papers by this authorWytse Wadman
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Search for more papers by this authorChris Van den Haute
Laboratory for Neurobiology and Gene Therapy, Center for Molecular Medicine and Leuven Brain Institute, KU Leuven, Leuven, Belgium
Leuven Viral Vector Core, Center for Molecular Medicine, KU Leuven, Leuven, Belgium
Search for more papers by this authorVeerle Baekelandt
Laboratory for Neurobiology and Gene Therapy, Center for Molecular Medicine and Leuven Brain Institute, KU Leuven, Leuven, Belgium
Search for more papers by this authorAlain G. Verstraete
Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium
Search for more papers by this authorKristl Vonck
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Search for more papers by this authorLars E. Larsen
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Search for more papers by this authorMathieu Sprengers
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Search for more papers by this authorEvelien Carrette
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Search for more papers by this authorJana Desloovere
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Search for more papers by this authorAlfred Meurs
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Search for more papers by this authorJean Delbeke
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Search for more papers by this authorChristian Vanhove
IBiTech, Department of Electronics and Information Systems, Ghent University, Ghent, Belgium
Search for more papers by this authorCorresponding Author
Robrecht Raedt
4BRAIN, Department of Head and Skin, Ghent University, Ghent, Belgium
Correspondence
Robrecht Raedt, 4BRAIN, Department of Head and Skin, Ghent University, Corneel Heymanslaan 10, Ghent, Belgium.
Email: [email protected].
Search for more papers by this authorSummary
Objective
One third of epilepsy patients do not become seizure-free using conventional medication. Therefore, there is a need for alternative treatments. Preclinical research using designer receptors exclusively activated by designer drugs (DREADDs) has demonstrated initial success in suppressing epileptic activity. Here, we evaluated whether long-term chemogenetic seizure suppression could be obtained in the intraperitoneal kainic acid rat model of temporal lobe epilepsy, when DREADDs were selectively expressed in excitatory hippocampal neurons.
Methods
Epileptic male Sprague Dawley rats received unilateral hippocampal injections of adeno-associated viral vector encoding the inhibitory DREADD hM4D(Gi), preceded by a cell-specific promotor targeting excitatory neurons. The effect of clozapine-mediated DREADD activation on dentate gyrus evoked potentials and spontaneous electrographic seizures was evaluated. Animals were systemically treated with single (.1 mg/kg/24 h) or repeated (.1 mg/kg/6 h) injections of clozapine. In addition, long-term continuous release of clozapine and olanzapine (2.8 mg/kg/7 days) using implantable minipumps was evaluated. All treatments were administered during the chronic epileptic phase and between 1.5 and 13.5 months after viral transduction.
Results
In the DREADD group, dentate gyrus evoked potentials were inhibited after clozapine treatment. Only in DREADD-expressing animals, clozapine reduced seizure frequency during the first 6 h postinjection. When administered repeatedly, seizures were suppressed during the entire day. Long-term treatment with clozapine and olanzapine both resulted in significant seizure-suppressing effects for multiple days. Histological analysis revealed DREADD expression in both hippocampi and some cortical regions. However, lesions were also detected at the site of vector injection.
Significance
This study shows that inhibition of the hippocampus using chemogenetics results in potent seizure-suppressing effects in the intraperitoneal kainic acid rat model, even 1 year after viral transduction. Despite a need for further optimization, chemogenetic neuromodulation represents a promising treatment prospect for temporal lobe epilepsy.
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose.
Supporting Information
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| epi16840-sup-0001-AppendixS1-S2.pdfPDF document, 412.3 KB | AppendixS1-S2 |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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