Long‐term chemogenetic suppression of seizures in a multifocal rat model of temporal lobe epilepsy

Objective One third of epilepsy patients do not become seizure-free using conventional medication. Therefore, there is a need for alternative treatments. Preclinical research designer receptors exclusively activated by drugs (DREADDs) has demonstrated initial success in suppressing epileptic activity. Here, we evaluated whether long-term chemogenetic seizure suppression could be obtained the intraperitoneal kainic acid rat model temporal lobe epilepsy, when DREADDs were selectively expressed excitatory hippocampal neurons. Methods Epileptic male Sprague Dawley rats received unilateral injections adeno-associated viral vector encoding inhibitory DREADD hM4D(Gi), preceded cell-specific promotor targeting The effect clozapine-mediated activation on dentate gyrus evoked potentials and spontaneous electrographic seizures was evaluated. Animals systemically treated with single (.1 mg/kg/24 h) or repeated mg/kg/6 clozapine. In addition, continuous release clozapine olanzapine (2.8 mg/kg/7 days) implantable minipumps All treatments administered during chronic phase between 1.5 13.5 months after transduction. Results group, inhibited treatment. Only DREADD-expressing animals, reduced frequency first 6 h postinjection. When repeatedly, suppressed entire day. Long-term treatment both resulted significant seizure-suppressing effects multiple days. Histological analysis revealed expression hippocampi some cortical regions. However, lesions also detected at site injection. Significance This study shows that inhibition hippocampus chemogenetics results potent model, even 1 year Despite further optimization, neuromodulation represents promising prospect epilepsy.