Mossy cells in temporal lobe epilepsy

摘要 摘要颞叶癫痫(TLE)是一种反复发作、使人衰弱的疾病，也是一种共病。 这极大地降低了生活质量。许多患者对药物反应不佳，这使得研究对 开发新的治疗方法。一个研究的焦点是海马体中称为齿状回的一部分。 (DG)，DG中的一种谷氨酸能细胞类型称为苔藓细胞(MC)。MCS有直接的兴奋性 投射到主要的神经细胞类型，颗粒细胞(GCs)，因此颗粒细胞在理论上处于重要地位 以规范DG在TLE中的作用。尽管MC可以兴奋GC，但许多研究人员认为MC-GC 兴奋性很弱。相反，MCs被认为主要激活抑制GCs的DG-GABA能神经元。在……里面 这一建议我们假设MC对GC的兴奋和抑制作用都具有重要的 角色，特别是当最初的侮辱导致TLE的时候。我们的中心假设是，在最初的侮辱中， GC的MC激发起着至关重要的作用，因为它极大地加强了GCs的激发，导致了 GC靶点和兴奋性毒性。相反，在慢性癫痫中，我们假设了一个非常不同的MC角色。 我们建议MCs恢复其正常作用，激活DG-GABA能神经元，抑制GCs， 从而减少慢性癫痫发作。因此，在最初的侮辱期间，MC应该被禁止 最佳结果，在慢性癫痫期间，应激活MC。如果得到支持，这一假设 将是一种范式转变，通过改变TLE中MC的观点。此外，拟议的实验将填补 知识上的重大差距，因为在最初的侮辱、潜伏期和慢性病期间对MC知之甚少 癫痫。 值得注意的是，MC调节正常小鼠的行为和认知任务。我们最近展示了MC对 与焦虑和认知相关的任务，这是TLE中的共病。因此，我们假设一个角色是 TLE行为合并症中的MCS。 总之，这些实验将挑战主流观点，填补关于MC的几个知识空白， DG和TLE。此外，这些实验可能会为治疗学带来新的方法。

ABSTRACT Temporal lobe epilepsy (TLE) is a disorder with recurrent, debilitating seizures as well as comorbidities that greatly decrease quality of life. Many patients respond poorly to medications, making research important to develop new treatments. A focus of research has been a part of the hippocampus called the dentate gyrus (DG), and a glutamatergic cell type in the DG called the mossy cell (MC). MCs have a direct excitatory projection to the main neuronal cell type, granule cells (GCs), so MCs are theoretically in an important position to regulate the role of the DG in TLE. Although MCs can excite GCs, many investigators consider MC-GC excitation is weak. Instead, MCs are thought to primarily activate DG GABAergic neurons that inhibit GCs. In this proposal we hypothesize that both the excitatory and inhibitory actions of MCs on GCs have important roles, particularly when an initial insult leads to TLE. Our central hypothesis is that during the initial insult, MC excitation of GCs plays a critical role because it strengthens greatly, leading to strong excitation of GC targets and excitotoxicity. In contrast, in chronic epilepsy, we hypothesize a very different MC role. We suggest that MCs resume their normal role to activate DG GABAergic neurons and inhibit GCs, which reduces chronic seizures. Therefore, during the initial insult, MCs should be inhibited for the best outcomes and during chronic epilepsy the MCs should be activated. If supported, this hypothesis would be a paradigm shift by changing the view of MCs in TLE. In addition, the proposed experiments will fill major gaps in knowledge because little is known about MCs during the initial insult, latent period, and chronic epilepsy. Notably, MCs regulate behavior and cognitive tasks in normal mice. We recently showed MCs regulate tasks related to anxiety and cognition, which are comorbidities in TLE. Therefore, we hypothesize a role of MCs in the behavioral comorbidities in TLE. Together these experiments will challenge prevailing views and fill several knowledge gaps about MCs, the DG, and TLE. Furthermore, the experiments will potentially give rise to new approaches for therapeutics.