Identification and reversal of primary and secondary epileptogenic changes

描述（由申请人提供）：阐明正常大脑转化为癫痫大脑的基本机制几十年来一直是癫痫研究的圣杯。如果癫痫发生的机制可以理解，那么新的治疗和疗法可以设计针对这些过程，以预防-并可能治愈-癫痫。虽然多年的研究已经揭示了癫痫发生过程中发生的许多变化，但一个基本问题是将介导癫痫发生的变化与与疾病相关的变化区分开来，但不起因果作用。这个问题对于几乎所有现有的癫痫模型都是明显的，这些模型产生广泛的脑损伤和细胞变化，从而使得疾病的近端原因难以确定。对于本提案，我们通过利用在该资助的第一个学期中产生的新型癫痫小鼠模型取得了关键性进展，其中癫痫在从海马齿状颗粒细胞（DGC）的子集（>5%）中有条件地、可诱导地缺失mTOR通路抑制剂磷酸酶和张力蛋白同源物（PTEN）后发展。mTOR通路的过度激活与颞叶癫痫的发展有关，这种缺失的作用-诱导新生儿DGC的异常整合-是重要的，因为异常的新生儿DGC是颞叶癫痫的标志性病理学，并且被怀疑引起疾病。我们的研究提供了DGC异常可导致癫痫的直接证据。 在证明异常DGC可能是癫痫的近端原因后，我们现在试图阐明这些细胞促进癫痫发作的机制。我们的指导性假设是，异常的DGC促进癫痫发生最初通过细胞内在的连接和活动的增加，其次通过诱导相邻颗粒细胞及其下游靶细胞之间的变化。为了验证这一假设，我们将确定SA 1异常细胞的主要特征，SA 2中原发性和继发性变化与癫痫发生之间的时间关联，以及SA 3和4中这些变化的功能意义。

DESCRIPTION (provided by applicant): Elucidating the basic mechanisms by which a normal brain is transformed into an epileptic brain has been a holy grail of epilepsy research for decades. If the mechanisms of epileptogenesis can be understood, then new treatments and therapies can be designed to target these processes to prevent - and possibly cure - epilepsy. While years of research have revealed a multitude of changes that occur during epileptogenesis, one basic problem has been distinguishing changes that mediate epileptogenesis from changes that are associated with the disease, but play no causal role. This problem is evident for almost all existing models of epilepsy, which produce widespread brain damage and cellular changes, thereby making the proximal cause of the disease difficult to ascertain. For the present proposal, we make a pivotal advance by utilizing a novel mouse model of epilepsy generated in the first term of this grant, in which epilepsy develops following conditional, inducible deletion of the mTOR pathway inhibitor phosphatase and tensin homologue (PTEN) from a subset (>5%) of hippocampal dentate granule cells (DGC). Excessive activation of the mTOR pathway is implicated in the development of temporal lobe epilepsy, and the effect of this deletion - to induce the abnormal integration of newborn DGC - is important because abnormal newborn DGC are a hallmark pathology of temporal lobe epilepsy, and are suspected of causing the disease. Our study provides direct evidence that abnormal DGC can cause epilepsy. Having demonstrating that abnormal DGC can be a proximal cause of epilepsy, we now seek to elucidate the mechanism(s) by which these cells promote seizures. Our guiding hypothesis is that abnormal DGCs promote epileptogenesis initially through cell-intrinsic increases in connectivity and activity, and secondarily by inducing changes among neighboring granule cells and their downstream targets. To test this hypothesis, we will determine the primary features of abnormal cells in SA1, the temporal associations between primary and secondary changes and epileptogenesis in SA2, and the functional significance of these changes in SA3 and 4.