Research ArticleEpilepsy

Optogenetic and Potassium Channel Gene Therapy in a Rodent Model of Focal Neocortical Epilepsy

Science Translational Medicine  21 Nov 2012:
Vol. 4, Issue 161, pp. 161ra152
DOI: 10.1126/scitranslmed.3004190

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Casting Light on the Shadow of Epilepsy

Epilepsy affects 1% of the population and is often resistant to medication. Surgery to remove the region of the brain that generates seizures is only feasible in a minority of cases because of risks to movement, language, vision, and other essential functions. There is an urgent need for alternative treatments. In a new study, Wykes et al. used a virus to express a therapeutic gene in a small number of brain neurons in the seizure-generating zone in a rat model of drug-resistant epilepsy. They also developed new wireless technology to monitor and detect seizures using a miniaturized implanted transmitter and advanced algorithms. They took two approaches to reduce brain circuit excitability and hence epileptic seizures in the rat model. First, to suppress neuronal firing acutely, they expressed the light-sensitive chloride transporter halorhodopsin in the seizure-generating zone. When laser light was delivered via an optic fiber to this region and the halorhodopsin was activated, they observed a decrease in electrical seizure activity. The success of this “optogenetic” approach implies that a device could be developed to detect and stop seizures “on demand” akin to an implantable defibrillator for heart rhythm disturbances. For longer-term suppression of epilepsy, the investigators overexpressed a brain potassium ion channel that normally regulates both neuronal excitability and neurotransmitter release. This gene therapy treatment fully prevented epilepsy from developing in the rat model. When it was applied during established epilepsy, potassium channel gene therapy progressively diminished the frequency of seizures until they stopped after a few weeks. Neither of the gene therapy approaches tested interfered with normal behavior, most likely because only a small number of neurons were targeted. Although still in the earliest stages of study, this gene therapy approach may hold promise for treating drug-resistant epilepsy.