Perisomatic inhibition in epilepsy

癫痫影响着全世界5000万人。在40%的颞叶癫痫（TLE）患者中，抗癫痫药物未能预防癫痫发作，增加了损伤、认知能力下降和死亡的风险。GABA能中间神经元（IN）的抑制功能受损是癫痫的一个重要病理机制，然而，我们对不同类型IN的网络功能的不完全理解限制了治疗策略的发展。篮状细胞的体周抑制控制兴奋性神经元放电的速率和同步性。这两种类型的篮状细胞，表达胆囊收缩素（CCK）或小清蛋白（PV），是同样丰富的，都保存在慢性癫痫。然而，为什么有两种不同的类体周IN，以及它们的功能如何在癫痫中改变，尚不清楚。候选人的长期目标是发展作为一个独立的神经科学家的职业生涯，以了解神经元微电路功能中的interneuron多样性的作用，以及各种interneuron亚型的功能障碍如何参与并导致癫痫。使用最近开发的工具来记录CCK和PV IN选择性地在清醒的行为动物中的活动，初步结果表明，在海马中，受TLE影响最大的脑区，CCK和PV IN在不同的脑状态下被招募。此外，在秒的时间尺度上，PV IN的活性与兴奋性神经元的活性正相关，而CCK IN的活性与兴奋性神经元的活性负相关，这表明CCK IN适合于控制整个网络的平均放电率和关联性。因此，目前提出的假设是，这两类体周IN在癫痫的不同脑状态中被招募，这可能导致选择性靶向CCK或PV IN的抗癫痫干预的不同结果。本建议提出了一个计划，以测试这一假设在慢性动物模型的颞叶癫痫（海马内红藻氨酸盐），使用体外电生理学和体内双光子钙成像与相关海马场电位记录，以：1）检验CCK和PV IN在癫痫的不同脑状态中被募集的假设;（2）验证兴奋性输入和相互抑制对PV和CCK IN的差异募集有贡献的假设;以及3）检验CCK IN在抑制TLE中的网络活动而不破坏空间信息的表征方面有效的假设。完成拟议的研究可能会通过以下方式推进该领域：1）建立以前未知的中间神经元活动的时间隔离; 2）确定潜在的电路机制; 3）确定CCK IN用于抗癫痫干预的疗效。此外，候选人提出个性化的计划，以获得科学背景（特别是在癫痫领域），研究方法（慢性癫痫模型和体外电生理学）和职业发展（拨款写作，教学和科学管理）的培训。斯坦福大学教授Ivan Soltesz的指导将为候选人成功开展研究和培训计划提供理想的环境，从而使候选人能够建立独立的研究计划。

Epilepsy affects 50 million people worldwide. In 40% of patients with temporal lobe epilepsy (TLE), antiepileptic drugs fail to prevent seizures, increasing the risk of injury, cognitive decline, and death. The impairment of inhibition by GABAergic interneurons (IN) is a key pathomechanism of epilepsy, however, our incomplete understanding of the network function of the diverse types of IN limits the development of treatment strategies. Perisomatic inhibition by basket cells controls the rate and synchrony of the firing of excitatory neurons. The two types of basket cells, expressing either cholecystokinin (CCK) or parvalbumin (PV), are equally abundant and are both preserved in chronic epilepsy. However, why there are two distinct classes of perisomatic IN, and how their function is altered in epilepsy, is not known. The candidate’s long-term goal is to develop a career as an independent neuroscientist to understand the role of interneuron diversity in neuronal microcircuit function, and how dysfunction in various interneuron subtypes is involved in and leads to epilepsy. Using recently developed tools to record the activity of CCK and PV IN selectively in awake, behaving animals, preliminary results show that in the hippocampus, the brain area most affected by TLE, CCK and PV IN are recruited in distinct brain states. Moreover, the activity of PV IN is correlated positively, while the activity of CCK IN is correlated negatively to the activity of excitatory neurons on the time scale of seconds, suggesting that CCK IN are suited to control average firing rates and associativity across the network. Therefore, the hypothesis of the current proposal is that the two classes of perisomatic IN are recruited in separate brain states in epilepsy, and this may lead to distinct outcome of antiepileptic interventions that selectively target CCK or PV IN. This proposal presents a plan to test this hypothesis in a chronic animal model of TLE (intrahippocampal kainate), using in vitro electrophysiology and in vivo 2-photon calcium imaging with correlated hippocampal field potential recording, to: 1) Test the hypothesis that CCK and PV IN are recruited in different brain states in epilepsy; 2) Test the hypothesis that excitatory inputs and reciprocal inhibition contribute to the differential recruitment of PV and CCK IN; and 3) Test the hypothesis that CCK IN are effective in dampening network activity in TLE without disrupting the representation of spatial information. Completion of the proposed study may advance the field by: 1) establishing a previously unknown temporal segregation of the activity of interneurons; 2) determining the underlying circuit mechanism; and 3) determining the efficacy of CCK IN for antiepileptic intervention. In addition, the candidate proposes a personalized plan to obtain training in scientific background (particularly in the epilepsy field), research methods (chronic epilepsy models and in vitro electrophysiology), and career development (grant writing, teaching and scientific management). The mentoring of Prof Ivan Soltesz at Stanford University will provide an ideal environment for the candidate to carry out the research and training plan successfully and thus will enable the candidate to establish an independent research program.