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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：
10599259
负责人：
Steve C Danzer
金额：
$ 47.05万
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599259
关键词：
Ablation Abnormal Cell Animal Model Animals Benchmarking Brain Brain Injuries Cell Count Cells Cessation of life Collecting Cell Development Diphtheria Toxin Disease Disinhibition Epilepsy Epileptogenesis Exhibits FLP recombinase FRAP1 gene Failure Frequencies Functional disorder Goals Grant Hippocampus 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 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.

项目总结/摘要阐明了正常大脑转变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能够被理解，那么新的治疗和疗法就可以针对这些过程来预防--甚至治愈-- 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，一个基本的问题是区分介导癫痫发生的变化和相关的变化，与疾病有关，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，这会造成广泛的脑损伤和细胞变化，从而使近端的原因，疾病难以确定。对于目前的建议，我们利用了一种新的小鼠癫痫模型，该补助金的第一个术语，其中自发性皮质癫痫发作在条件性，诱导性 mTOR通路抑制剂磷酸酶和张力蛋白同源物（PTEN）从海马的>9%的缺失齿状颗粒细胞这种缺失的影响-诱导新生颗粒细胞的异常整合 - 是重要的，因为异常的新生颗粒细胞是颞叶癫痫的标志性病理学，并被怀疑是致病原因我们的模型提供了直接证据，表明异常颗粒细胞可以导致癫痫，并创造了一个机会来了解他们是如何导致疾病的。对这个模型的研究使我们假设颞叶癫痫的自发性发作结果从内在的过度兴奋颗粒细胞和受损的抑制控制的组合作用这些细胞。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一个独特的功能， PTEN敲除模型：操纵异常颗粒细胞的数量或“负载”的能力。我们将产生其中5-8%的颗粒细胞缺乏PTEN的动物。这些动物的海马生理学，但不是明显的皮质癫痫发作。这是第一个“打击”。然后我们将挑战这些改变了的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的回路-第二次打击。我们预测去抑制作用将与PTEN敲除颗粒细胞协同作用，使细胞不稳定。海马回路和促进癫痫发作。这些研究将提供一个概念验证测试，叶癫痫的发展，并将提供深入了解治疗策略。

项目成果

期刊论文数量（39）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hippocampal interneurons are direct targets for circulating glucocorticoids.

DOI：
10.1002/cne.25322
发表时间：
2022-08
期刊：
JOURNAL OF COMPARATIVE NEUROLOGY
影响因子：
2.5
作者：
Kraus, Kimberly L.;Chordia, Arihant P.;Drake, Austin W.;Herman, James P.;Danzer, Steve C.
通讯作者：
Danzer, Steve C.

Impact of corticosterone treatment on spontaneous seizure frequency and epileptiform activity in mice with chronic epilepsy.

DOI：
10.1371/journal.pone.0046044
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Castro OW;Santos VR;Pun RY;McKlveen JM;Batie M;Holland KD;Gardner M;Garcia-Cairasco N;Herman JP;Danzer SC
通讯作者：
Danzer SC

Contributions of Adult-Generated Granule Cells to Hippocampal Pathology in Temporal Lobe Epilepsy: A Neuronal Bestiary.

DOI：
10.3233/bpl-170056
发表时间：
2018-08-10
期刊：
Brain plasticity (Amsterdam, Netherlands)
影响因子：
0
作者：
Danzer SC
通讯作者：
Danzer SC

RU486 Mitigates Hippocampal Pathology Following Status Epilepticus.

DOI：
10.3389/fneur.2016.00214
发表时间：
2016
期刊：
Frontiers in neurology
影响因子：
3.4
作者：
Wulsin AC;Herman JP;Danzer SC
通讯作者：
Danzer SC

Functional disruption of stress modulatory circuits in a model of temporal lobe epilepsy.

DOI：
10.1371/journal.pone.0197955
发表时间：
2018
期刊：
PloS one
影响因子：
3.7
作者：
Wulsin AC;Franco-Villanueva A;Romancheck C;Morano RL;Smith BL;Packard BA;Danzer SC;Herman JP
通讯作者：
Herman JP