Optical containment of epilepsy using Two-Photon-Light

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Current pharmacological treatment approaches for patients suffering from epileptic seizures comprise modulators at excitatory and inhibitory synapses. However, despite great therapeutical advances a substantial part of epilepsies is remaining refractory to medical treatment. In addition, all available antiepileptic drugs exert their effects unspecifically and therefore principally affect the entire brain. At the same time, the cortex is a complex circuit composed of a wide range of neuronal subtypes with very different morphological and functional features. Given this heterogeneity it is likely that different neuronal subtypes have very different, maybe even opposite effects on the spread of seizures. Thus, more specific and more efficient novel therapeutic approaches are urgently needed.Over the past few decades evidence has accumulated that cortical inhibition mediates local containment of ictal events and that the spreading of epileptic discharges is related to the failure of the inhibitory surrounding of an epileptic focus. Due to technical restrictions, our knowledge of cellular events that affect origination, propagation and termination of epileptic seizures, has remained highly unsatisfactory. The research project supposed here seeks to identify the function of specific cells during an ictal event by combining highly sophisticated two-photon-imaging with the spatially precise optical modulation of even single cortical cells by application of chemically caged neurotransmitters that are photo-releasable. The investigatory work will focus on the so-called Chandelier cells that are thought to be the most powerful inhibitory influencers of excitatory Pyramidal cells. Pyramidal cells play a key role in the initiation of an epileptiform event. The proposed project represents a major departure from traditional therapeutic approaches to seizures disorders, because it will target a specific cell population rather than the entire brain, as it happens in current pharmacological therapies. The results of this project could potentially lead to a paradigm shift in how we treat epilepsy.