The Role of Hippocampal area CA2 in Epilepsy

海马区 CA2 在癫痫中的作用

基本信息

批准号：
10745170
负责人：
Helen E Scharfman
金额：
$ 59.47万
依托单位：
NATHAN S. KLINE INSTITUTE FOR PSYCH RES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10745170
关键词：
Acute Address Anatomy Animal Model Area Cations Characteristics Chronic Development Dorsal Drug resistance Epilepsy Frequencies Funding Genes Genetic Genetic Models Goals HCN1 channel HCN1 gene Hippocampus Human Intervention Intractable Epilepsy Ion Channel Gating Left Memory Modeling Molecular Mus Mutation Nerve Degeneration Patients Pattern Pilocarpine Play Potassium Channel Property Public Health Rodent Rodent Model Role Sclerosis Seizures Site Slice Source Status Epilepticus Synapses Temporal Lobe Epilepsy Testing Therapeutic Tonic - clonic seizures Up-Regulation Variant dentate gyrus epileptic encephalopathies experimental study functional restoration genetic variant hippocampal pyramidal neuron human model improved in vivo kainate mouse model new therapeutic target novel novel therapeutic intervention optogenetics potassium channel protein TREK-1 pre-clinical response selective expression social synaptic inhibition therapeutic target voltage

项目摘要

ABSTRACT A deeper understanding of the molecular, cellular, and circuit mechanisms that contribute to intractable epilepsy is of critical importance for improving existing therapeutic approaches. Rodent epilepsy models provide an important approach for achieving this goal and for the preclinical exploration of novel treatments. Here we focus on two types of mouse models relevant to drug-resistant seizure disorders in humans: the pilocarpine status epilepticus model (PILO-SE) of acquired temporal lobe epilepsy (TLE) and a mouse model with a genetic variant in voltage-gated ion channels that cause seizure disorders in humans. TLE shows a characteristic pattern of hippocampal neurodegeneration termed mesial temporal sclerosis (MTS), with substantial loss of pyramidal neurons in the CA1 and CA3 regions and a relative sparing of dentate gyrus (DG) and CA2 regions. Survival of DG and CA2 has led to the hypotheses that both are important for seizure activity. Although the role of DG has been well studied in rodent models, the role of CA2 has remained relatively unexplored. In the previous funding period, we found that PILO-SE leads to increased overall CA2 excitation, due to increased intrinsic excitability, enhanced synaptic excitation from DG and reduced synaptic inhibition. Importantly, we found that chronic chemogenetic or acute closed-loop optogenetic silencing of CA2 led to a significant decrease in seizure activity in PILO-SE mice. However, our previous analyses were restricted to dorsal CA2. We will address here the role of ventral CA2, as studies in both humans and rodent models suggest that ventral hippocampus may be an even more important site for seizures in TLE than dorsal hippocampus. We will therefore investigate the hypothesis that chemogenetic and/or optogenetic silencing of ventral CA2 will be even more effective in reducing seizures than observed upon silencing dorsal CA2. Our previous studies also left open the question as to whether the increase in CA2 excitation in PILO-SE is causally related to the role of CA2 in seizures. We will address this question by asking whether interventions that restore normal levels of CA2 intrinsic excitability can rescue seizures in PILO-SE. Such experiments have the advantage over genetic-based silencing as they will not interfere with the normal role of CA2 in hippocampal-dependent social memory. In addition to acquired forms of epilepsy, an increasing number of cases of epilepsy have been shown to be caused by genetic variants, some associated with MTS and others without MTS. Here we address whether CA2 may play a more general role in seizure activity by investigating its role in a mouse model of a genetic form of epilepsy caused by mutations in the gene encoding the HCN1 voltage-gated ion channel, and testing whether CA2 silencing can suppress seizures in this model. The experiments of this proposal thus offer the promise of further validating CA2 as target for novel therapeutic approaches for treatment of a range of seizure disorders.

抽象的更深入地了解导致棘手问题的分子、细胞和电路机制癫痫对于改善现有的治疗方法至关重要。啮齿类动物癫痫模型为实现这一目标和新疗法的临床前探索提供了重要方法。在这里，我们重点关注与人类耐药性癫痫症相关的两种小鼠模型：获得性颞叶癫痫 (TLE) 毛果芸香碱癫痫持续状态模型 (PILO-SE) 和小鼠模型电压门控离子通道的遗传变异会导致人类癫痫发作。 TLE 显示海马神经变性的特征模式，称为内侧颞叶硬化症 (MTS)，CA1 和 CA3 区域锥体神经元大量丧失，相对较少齿状回 (DG) 和 CA2 区域。 DG 和 CA2 的存活导致了以下假设：对于癫痫发作活动很重要。尽管 DG 的作用已在啮齿动物模型中得到充分研究，但 CA2 的作用仍然相对未被探索。在之前的资助期间，我们发现 PILO-SE 导致增加整体 CA2 兴奋，由于内在兴奋性增加、DG 突触兴奋增强和减少突触抑制。重要的是，我们发现慢性化学遗传学或急性闭环光遗传学 CA2 沉默导致 PILO-SE 小鼠癫痫发作活动显着降低。然而，我们之前的分析仅限于背侧 CA2。我们将在这里讨论腹侧的作用 CA2，对人类和啮齿动物模型的研究表明，腹侧海马可能是一个更重要的区域。 TLE 中癫痫发作的重要部位比背侧海马更重要。因此，我们将研究以下假设：腹侧 CA2 的化学遗传学和/或光遗传学沉默在减少癫痫发作方面比在沉默背侧 CA2 后观察到。我们之前的研究也留下了一个问题： PILO-SE 中 CA2 兴奋的增加与 CA2 在癫痫发作中的作用有因果关系。我们将解决这个问题通过询问恢复 CA2 内在兴奋性正常水平的干预措施是否可以挽救 PILO-SE 中的癫痫发作。此类实验比基于基因的沉默具有优势，因为它们不会干扰 CA2 在海马依赖性社会记忆中的正常作用。除了获得性癫痫之外，越来越多的癫痫病例已被证明由遗传变异引起，一些与 MTS 相关，另一些则与 MTS 无关。在这里我们解决通过研究 CA2 在癫痫发作的小鼠模型中的作用，CA2 是否可能在癫痫发作活动中发挥更普遍的作用由编码 HCN1 电压门控离子通道的基因突变引起的遗传形式癫痫，以及测试 CA2 沉默是否可以抑制该模型中的癫痫发作。因此，该提案的实验为进一步验证 CA2 作为新型靶点提供了希望。治疗一系列癫痫疾病的治疗方法。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Enhanced excitability of the hippocampal CA2 region and its contribution to seizure activity in a mouse model of temporal lobe epilepsy.

DOI：
10.1016/j.neuron.2022.07.020
发表时间：
2022-10-05
期刊：
NEURON
影响因子：
16.2
作者：
Whitebirch, Alexander C.;LaFrancois, John J.;Jain, Swati;Leary, Paige;Santoro, Bina;Siegelbaum, Steven A.;Scharfman, Helen E.
通讯作者：
Scharfman, Helen E.