Identification and reversal of primary and secondary epileptogenic changes

原发性和继发性致癫痫变化的识别和逆转

基本信息

批准号：
9816799
负责人：
Steve C Danzer
金额：
$ 47.84万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9816799
关键词：
Ablation Abnormal Cell Animal Model Animals Benchmarking Brain Brain Injuries Cell Count Cells Cessation of life Development Diphtheria Toxin Disease Disinhibition Epilepsy Epileptogenesis Exhibits FLP recombinase FRAP1 gene Failure Frequencies Functional disorder Goals Grant Hippocampus (Brain)Human Impairment In Vitro Interneurons Knock-out Knockout Mice Lead Mediating Methods Modeling Monitor Mus National Institute of Neurological Disorders and Stroke Neurons Newborn Infant PTEN gene Parents Pathology Pathway interactions Perforant Pathway Physiology Play Process Recurrence Research Research Personnel Role Seizures Series Severities Slice Temporal Lobe Temporal Lobe Epilepsy Testing Therapeutic Viral Work brain malformation combinatorial density design designer receptors exclusively activated by designer drugs diphtheria toxin receptor experimental study granule cell in vivo inhibitory neuron insight intersectionality knockout animal meetings mouse model neuron loss novel phosphatase inhibitor prevent receptor expression

项目摘要

Project Summary/Abstract 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 utilize a novel mouse model of epilepsy generated in the first term of this grant, in which spontaneous cortical seizures develop following conditional, inducible deletion of the mTOR pathway inhibitor phosphatase and tensin homologue (PTEN) from >9% of hippocampal dentate granule cells. The effect of this deletion – to induce the abnormal integration of newborn granule cells – is important because abnormal newborn granule cells are a hallmark pathology of temporal lobe epilepsy, and are suspected of causing the disease. Our model provides direct evidence that abnormal granule cells can cause epilepsy, and creates an opportunity to understand how they cause the disease. Work with this model has led us to hypothesize that spontaneous seizures in temporal lobe epilepsy result from the combinatorial effects of intrinsically hyperexcitable granule cells and impaired inhibitory control of these cells. To test this two-hit model of epileptogenesis, we will make full use of a unique feature of our PTEN knockout model: the ability to manipulate the number or “load” of abnormal granule cells. We will generate animals in which 5-8% of granule cells lack PTEN. These animals exhibit abnormal hippocampal physiology, but not overt cortical seizures. This constitutes the first “hit”. We will then challenge these altered circuits by silencing distinct classes of hippocampal inhibitory interneurons in vitro and in vivo – the second hit. We predict that disinhibition will act synergistically with PTEN knockout granule cells to destabilize the hippocampal circuit and promote seizures. The studies will provide a proof-of-concept test for how temporal lobe epilepsy develops, and will provide insights into therapeutic strategies.

项目概要/摘要阐明正常大脑转变为癫痫大脑的基本机制已经几十年来一直是癫痫研究的圣杯如果癫痫发生的机制能够被理解，然后可以设计新的治疗方法和疗法来针对这些过程来预防 - 并可能治愈 - 虽然多年的研究揭示了癫痫发生过程中发生的多种变化，但其中之一是基本问题是区分介导癫痫发生的变化和相关的变化与该疾病有关，但对几乎所有现有的癫痫模型来说，这个问题都没有因果关系，它会产生广泛的脑损伤和细胞变化，从而使对于目前的建议，我们利用了一种新的癫痫小鼠模型。该拨款的第一期，其中自发性皮质癫痫发作是在有条件的、诱导的从 >9% 的海马中删除 mTOR 通路抑制剂磷酸酶和张力蛋白同源物 (PTEN) 齿状颗粒细胞的这种缺失的作用——诱导新生颗粒细胞的异常整合。 – 很重要，因为异常的新生儿颗粒细胞是颞叶癫痫的标志性病理学，我们的模型提供了异常颗粒细胞可以引起这种疾病的直接证据。导致癫痫，并创造了了解它们如何导致该疾病的机会。利用这个模型，我们发现了颞叶癫痫的自发性癫痫发作由本质上过度兴奋的颗粒细胞和受损的抑制控制的组合效应引起为了测试这种癫痫发生的两次打击模型，我们将充分利用我们的独特功能。 PTEN 敲除模型：操纵异常颗粒细胞的数量或“负载”的能力。产生 5-8% 颗粒细胞缺乏 PTEN 的动物这些动物表现出异常的海马体。生理学，但不是明显的皮质癫痫，这构成了第一个“打击”，然后我们将挑战这些改变。通过在体外和体内沉默不同类别的海马抑制性中间神经元来控制回路——第二个打击。我们预测去抑制将与 PTEN 敲除颗粒细胞协同作用，从而破坏细胞的稳定性。这些研究将为时间性机制提供概念验证测试。叶性癫痫的发展将为治疗策略提供见解。