Mossy cell control of adult neurogenesis in epilepsy

苔藓细胞控制癫痫成人神经发生

基本信息

  • 批准号:
    10259662
  • 负责人:
  • 金额:
    $ 3.43万
  • 依托单位:
  • 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:
    2018-05-01 至 2021-10-31
  • 项目状态:
    已结题

项目摘要

Epilepsy results from an imbalance in neuronal excitation and inhibition within the brain. One of the most common forms of epilepsy is temporal lobe epilepsy (TLE), and a large percentage of TLE patients are refractory to medical treatment. TLE is associated with cell loss, gliosis, altered neurogenesis, axon sprouting, and synaptic reorganization in both humans and animal models of TLE. These changes are best described in the hippocampus, which becomes hyperexcitable in epilepsy and can serve as an initiating seizure focus in TLE. In rodent models, there is increased proliferation of adult-born neurons in the hippocampus in TLE, and these new neurons integrate abnormally into neuronal circuits and are believed to contribute to epileptogenesis. Glutamatergic signaling and synapse formation are critical for the proper maturation, synaptic integration, and survival of adult-born dentate granule cells (DGCs), and a recent study demonstrated that hilar mossy cells serve as the first glutamatergic inputs to adult-born DGCs. Interestingly, these hippocampal mossy cells are also highly susceptible to apoptosis after seizures. This suggests that the loss of mossy cells after status epilepticus could alter the maturation and synapse formation by adult-born DGCs and thus the loss of these cells may be a critical step in pathogenesis of epilepsy via its effect on post-seizure neurogenesis. This proposal will investigate how mossy cells contribute to the normal maturation and network integration of adult- born granule cells, and whether mossy cell loss contributes to the abnormal synaptic integration, maturation, and survival of adult-born DGCs in epilepsy. In addition, we will directly test whether the rescue of mossy cell loss prevents alterations in neurogenesis and the development of epilepsy. We will use a mossy cell specific Cre driver mouse line to selectively modify mossy cell activity and survival using pharmacogenetics, diphtheria toxin-mediated cell ablation, and inhibition of apoptosis, and assess changes in adult-born DGC synaptic integration and survival. Additionally, we will combine these techniques with the well-established pilocarpine model of TLE, to assess how mossy cell death affects adult-born DGC maturation and epileptogenesis. We hypothesize that mossy cell activity is critical for proper integration, maturation, and survival of adult-born granule cells and that a reduction in mossy cell loss will restore these features and reduce epileptogenesis after status epilepticus in mice. This study will not only greatly improve our understanding of the role of mossy cells in neurogenesis and epilepsy, but could lead to the development of new therapeutic strategies for many types of refractory epilepsies.
癫痫是由于大脑内神经元兴奋和抑制的不平衡引起的。一个最 癫痫的常见形式是颞叶癫痫(TLE),并且很大比例的TLE患者是 药物治疗无效。TLE与细胞丢失、神经胶质增生、神经发生改变、轴突发芽有关, 以及人类和动物TLE模型中的突触重组。这些变化在 海马体,在癫痫中变得过度兴奋,可以作为癫痫发作的起始病灶, TLE。在啮齿类动物模型中,TLE海马中成年神经元的增殖增加, 这些新的神经元异常地整合到神经元回路中, 癫痫发生谷氨酸能信号传导和突触形成对于突触的适当成熟、突触的形成和突触的形成是至关重要的。 整合和成年出生的齿状颗粒细胞(DGC)的存活,最近的研究表明, 苔藓状细胞作为第一个神经元能输入到成人出生的DGC。有趣的是,这些海马苔藓 细胞在癫痫发作后对凋亡也高度敏感。这表明,苔藓细胞的损失后, 癫痫持续状态可以改变成年DGC的成熟和突触形成,从而使DGC的功能丧失。 这些细胞可能通过其对癫痫发作后神经发生的影响而成为癫痫发病机制中的关键步骤。这 该提案将研究苔藓细胞如何促进成年人的正常成熟和网络整合, 出生的颗粒细胞,以及苔藓细胞的损失是否有助于异常的突触整合,成熟, 和癫痫患者中成人DGC的存活率。此外,我们将直接测试苔藓细胞的拯救是否 这种缺失阻止了神经发生的改变和癫痫的发展。我们将使用苔藓细胞特异性 Cre驱动小鼠系选择性地修改苔藓细胞活性和生存使用药物遗传学,白喉 毒素介导的细胞消融和细胞凋亡的抑制,并评估成人出生的DGC突触的变化。 融合与生存。此外,我们将联合收割机这些技术与成熟的毛果芸香碱 TLE模型,以评估苔藓细胞死亡如何影响成年出生的DGC成熟和癫痫发生。我们 假设苔藓细胞活性对于成年出生的正常整合、成熟和存活至关重要 颗粒细胞和苔藓细胞损失的减少将恢复这些特征并减少癫痫发生 在小鼠癫痫持续状态之后。这项研究不仅将大大提高我们对苔藓作用的认识 细胞在神经发生和癫痫,但可能导致新的治疗策略的发展,许多 难治性癫痫的类型

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Does Delayed Microglial Ablation Alter Outcomes after Traumatic Brain Injury?
延迟小胶质细胞消融会改变脑外伤后的结果吗?
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{{ truncateString('CORWIN BUTLER', 18)}}的其他基金

Role of hippocampal interneurons in aberrant neurogenesis and epilepsy after traumatic brain injury
海马中间神经元在脑外伤后异常神经发生和癫痫中的作用
  • 批准号:
    10590467
  • 财政年份:
    2023
  • 资助金额:
    $ 3.43万
  • 项目类别:
Mossy cell control of adult neurogenesis in epilepsy
苔藓细胞控制癫痫成人神经发生
  • 批准号:
    9912852
  • 财政年份:
    2018
  • 资助金额:
    $ 3.43万
  • 项目类别:

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