Optogenetic and chemogenetic therapies for epilepsy.

Drug-resistant epilepsy remains a significant health-care burden. The most effective treatment is surgery, but this is suitable for very few patients because of the unacceptable consequences of removing brain tissue. In contrast, gene therapy can regulate neuronal excitability in the epileptic focus whilst preserving function. Optogenetics and chemogenetics have the advantage that they are titratable therapies. Optogenetics uses light to control the excitability of specific neuronal populations. Optogenetics can be used in a closed-loop paradigm in which the light source is activated only when seizures are detected. However, expression of foreign proteins raises concerns about immunogenicity. Chemogenetics relies on the modification of an endogenous receptor or the production of a modified chimeric receptor that responds to an exogenous ligand. The main chemogenetic approach applied to epilepsy is to use designer receptors exclusively activated by designer drugs (DREADDs), which have been mainly modified muscarinic receptors or kappa-opioid receptors. Genetically modified human muscarinic receptor DREADDs are activated not by acetylcholine but by specific drugs such as clozapine-n-oxide or olanzepine. The dose of the drugs can be titrated in order to suppress seizures without adverse effects. Lastly, there is a chemogenetic approach that is activated by an endogenous ligand, glutamate. This takes advantage of invertebrate glutamate receptors that are chloride permeable. These bind glutamate released during seizure activity, and the resultant chloride current inhibits neuronal activity. The exogenous ligand, ivermectin, can also be given to reduce neuronal activity either chronically or as a rescue medication. The translation of this technology is hampered by the expression of a foreign protein. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.