Optical containment of epilepsy using Two-Photon-Light

目前用于患有癫痫发作的患者的药理学治疗方法包括兴奋性和抑制性突触的调节剂。然而，尽管有很大的治疗进展，相当一部分癫痫仍然是难治性的药物治疗。此外，所有可用的抗癫痫药物都不特异性地发挥作用，因此主要影响整个大脑。同时，皮层是一个复杂的回路，由各种各样的神经元亚型组成，具有非常不同的形态和功能特征。鉴于这种异质性，不同的神经元亚型可能对癫痫发作的传播具有非常不同的，甚至可能相反的影响。因此，更具体，更有效的新的治疗方法是迫切需要的。在过去的几十年里，越来越多的证据表明，皮层抑制介导的局部遏制发作事件和癫痫放电的蔓延是有关的抑制周围的癫痫focus.In失败。由于技术上的限制，我们对影响癫痫发作的起源、传播和终止的细胞事件的了解仍然非常不令人满意。这里假设的研究项目旨在通过将高度复杂的双光子成像与空间精确的光学调制相结合来确定特定细胞在发作事件期间的功能，即使是单个皮层细胞，也是通过应用化学笼状神经递质来实现的。解释性工作将集中在所谓的吊灯细胞，被认为是最强大的抑制性影响兴奋性锥体细胞。锥体细胞在癫痫样事件的起始中起关键作用。拟议的项目代表了对癫痫发作疾病的传统治疗方法的重大偏离，因为它将靶向特定的细胞群，而不是整个大脑，因为它发生在当前的药物治疗中。该项目的结果可能会导致我们如何治疗癫痫的范式转变。

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.