Perisomatic inhibition in epilepsy

全世界有5000万人患有癫痫。在40%的颞叶癫痫（TLE）患者中，抗癫痫药物不能预防癫痫发作，从而增加了损伤、认知能力下降和死亡的风险。GABAergic interneuron （IN）的抑制功能受损是癫痫的一个关键病理机制，然而，我们对不同类型IN的网络功能的不完全了解限制了治疗策略的发展。篮状细胞的胞周抑制控制兴奋性神经元放电的速率和同步。这两种表达胆囊收缩素（CCK）或小白蛋白（PV）的篮状细胞同样丰富，并且在慢性癫痫中都有保存。然而，为什么有两种不同类型的核周围素，以及它们在癫痫中的功能如何改变，目前尚不清楚。候选人的长期目标是发展成为一名独立的神经科学家，以了解中间神经元多样性在神经元微电路功能中的作用，以及各种中间神经元亚型的功能障碍如何参与并导致癫痫。利用最近开发的工具选择性地记录清醒、行为动物的CCK和PV IN的活动，初步结果表明，在海马中，受TLE、CCK和PV IN影响最大的大脑区域在不同的大脑状态下被招募。此外，PV IN的活性与兴奋性神经元的活性在秒尺度上呈正相关，而CCK IN的活性与兴奋性神经元的活性呈负相关，表明CCK IN适合控制整个网络的平均放电率和联想性。因此，目前提出的假设是，癫痫患者在不同的大脑状态下招募了两类核周围IN，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。本研究拟采用体外电生理和体内双光子钙成像技术，结合相关海马场电位记录，在TLE（海马内盐）慢性动物模型中验证这一假说：1)验证CCK和PV in在癫痫患者不同脑状态下被募集的假说；2)验证兴奋性输入和相互抑制导致PV和CCK IN的差异募集的假设；3)验证CCK IN在不破坏空间信息表征的情况下有效抑制TLE网络活动的假设。这项研究的完成可能会推动该领域的发展：1)建立一个以前未知的中间神经元活动的时间隔离；2)确定底层电路机制；3)确定CCK IN的抗癫痫干预效果。此外，候选人还提出了在科学背景（特别是癫痫领域）、研究方法（慢性癫痫模型和体外电生理）和职业发展（基金写作、教学和科学管理）方面获得培训的个性化计划。斯坦福大学教授Ivan Soltesz的指导将为候选人成功实施研究和培训计划提供理想的环境，从而使候选人能够建立一个独立的研究计划。

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.