Optogenetic hub cell control for no seizures, no side-effects in temporal lobe ep

描述（由申请人提供）：颞叶癫痫是成人癫痫最常见的形式。目前可用的抗癫痫药物通常具有显著的和使人衰弱的副作用，并且颞叶癫痫经常变得对药物治疗具有抗性，呈现出巨大的社会和医学问题。拟议研究背后的中心思想是，只有在关键时刻，通过暂时抑制少数独特神经元的活动，才有可能实现癫痫控制，这些神经元可能主要负责触发边缘系统中的癫痫发作。我们最近的大规模计算建模研究表明，罕见的，异常的，超连接的，枢纽样神经元可能在癫痫发作的启动中发挥关键作用。随后，这种中枢细胞在健康发育的海马体中得到了证实，并且已经表明，切片中单个中枢细胞的调节可以阻断整个网络的自发爆发活动。在这里，我们提出使用新的光遗传学方法来选择性地抑制癫痫成年小鼠体内齿状回和内嗅皮层中的异常中枢样细胞，以防止内嗅-海马网络内的连合-联合和颞-氨通路的过度激活，特别是在自发性复发性癫痫发作时。因为操作将以时间选择性方式仅影响整个边缘系统中的少数细胞，所以可以在对电路的正常信息处理的影响最小的情况下实现有效的癫痫控制。如果成功，拟议的研究将展示一种从根本上新颖的方法，以实现“无癫痫发作，无副作用”的癫痫治疗目标。

DESCRIPTION (provided by applicant): Temporal lobe epilepsy is the most common form of epilepsy in adults. Currently available anti-epileptic drugs often have significant and debilitating side-effects, and temporal lobe epilepsy frequently becomes resistant to drug therapy, presenting an enormous social and medical problem. The central idea behind the proposed research is that it may be possible to achieve seizure control by transiently inhibiting, only at critical moments, the activity of a low number of unique neurons that may be primarily responsible to triggering seizures in the limbic system. Our recent large-scale computational modeling studies have shown that rare, abnormal, super- connected, hub-like neurons may play a key role in seizure initiation. Subsequently, such hub cells have been demonstrated in the healthy developing hippocampus, and it has been shown that modulation of single hub cells in slices can block the spontaneous bursting activity of the entire network. Here we propose to use novel optogenetic approaches to selectively inhibit abnormal hub-like cells in the dentate gyrus and entorhinal cortex of epileptic adult mice in vivo in order to prevent the hyper-activation of the commissural-associational and temporo-ammonic pathways within the entorhino-hippocampal network specifically at the onset of spontaneous recurrent seizures. Because the manipulation will affect only a few cells in the entire limbic system in a temporally selective manner, effective seizure control may be achieved with minimal effects on the normal information processing of the circuit. If successful, the proposed research will demonstrate a fundamentally novel approach to achieving the goal of "no seizures, no side-effects" for the treatment of epilepsy.