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Semaphorin-dependent GABAergic synapse formation: A novel approach to increasing inhibition in the intact brain

Semaphorin-dependent GABAergic synapse formation: A novel approach to increasing inhibition in the intact brain
信号蛋白依赖性 GABA 能突触形成:一种增强完整大脑抑制的新方法
批准号:
10119391
负责人:
SUZANNE PARADIS
金额:
$58.77万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2010
资助国家:
美国
项目状态:
已结题
起止时间:
2010-08-01 至 2021-04-30

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中文摘要
翻译
总结 我们建议利用Sema4D信号的突触发生潜力来增加GABA能突触, 数量,从而增强神经回路的抑制作用并抑制癫痫发作。这种方法可以 有益于预防癫痫的形成、阻止其进展或抑制过度兴奋 在癫痫发作期间 以前我的实验室发现分泌蛋白Semaphorin 4D(Sema4D)驱动抑制性突触 在海马神经元和从海马神经元培养的切片中, 产前和新生儿海马体。我们还证明了海马内注入 Sema4D的细胞外结构域进入成年海马迅速促进新的 GABA能突触。重要的是,这些数据表明,分子机制调节 年轻海马体中的GABA能突触发生在成年后仍有功能, 可以用来调节网络的兴奋性。我们直接通过证明这一点来解决这一问题, Sema4D治疗可防止由海马直接电刺激或 静脉注射致惊厥药戊四氮此外,我们发现Sema4D治疗 在难治性癫痫持续状态的啮齿动物模型中恢复了地西泮的功效。 鉴于这些研究的成功,我的实验室进行了一个新的实验方向,以确定是否 Sema4D治疗对人类癫痫具有治疗潜力。我们将把工作重点放在可译性上 Sema4D作为抗癫痫治疗剂用于治疗癫痫持续状态(SE)。不幸的是,大约 30%的SE患者对当前药物(包括苯二氮卓类)治疗难治。一 关于癫痫持续状态不应性起源的假说是,延长的神经去极化导致 细胞表面GABAA受体的内化,从而降低响应于 GABA能信号传导(Joshi & Kapur,2012)。我们假设,通过急剧增加 使用Sema4D治疗抑制性突触,我们可以维持或重新建立苯二氮卓类 这些人大脑中的敏感性。第二,为了进一步我们的体内小鼠研究, Sema4D依赖性癫痫发作抑制,并进一步翻译我们的研究结果,我们将探讨 向小鼠施用Sema4D(例如静脉内注射编码Sema4D的病毒)的替代方法。 最后,我们将通过询问Sema4D是否促进啮齿动物中的Sema4D来测试我们的发现的可翻译性。 抑制人类神经元突触形成。
英文摘要
SUMMARY We propose to harness the synaptogenic potential of Sema4D signaling to increase GABAergic synapse number, thus enhancing inhibition in neural circuits and suppressing seizures. This approach could be beneficial to preventing the establishment of epilepsy, halting its progression, or suppressing hyperexcitability during a seizure event. Previously my lab discovered that the secreted protein Semaphorin 4D (Sema4D) drives inhibitory synapse formation on a remarkably fast time scale (i.e. minutes) in hippocampal neurons and slice cultured from the pre-natal and neonatal hippocampus. We also demonstrated that intra-hippocampal infusion of the extracellular domain of Sema4D into the adult hippocampus rapidly promotes the formation of new GABAergic synapses. Importantly, these data demonstrate that the molecular machinery regulating GABAergic synaptogenesis in the young hippocampus remains functional in the adult and that this machinery can be harnessed to modulate network excitability. We directly addressed this point by demonstrating that Sema4D treatment protects against seizures induced by direct electrical stimulation of the hippocampus or by intravenous infusion of the proconvulsant drug pentylenetetrazol. Further, we found that Sema4D treatment restored the efficacy of diazepam in a rodent model of refractory status epilepticus. Given the success of these studies, my laboratory has undertaken a new experimental direction to determine if Sema4D treatment has therapeutic potential for human epilepsies. We will focus our work on the translatability of Sema4D as an anti-seizure therapeutic for treating status epilepticus (SE). Unfortunately, approximately 30% of patients with SE are refractory to treatment with current medications including benzodiazepines. One hypothesis about the origin of refractoriness in status epilepticus is that prolonged neural depolarization leads to internalization of cell-surface GABAA receptors, thus reducing total inhibitory current in response to GABAergic signaling (Joshi & Kapur, 2012). We hypothesize that by acutely increasing the number of inhibitory synapses using Sema4D treatment, we could maintain or re-establish benzodiazepine sensitivity in the brains of these individuals. Second, in order to further our in vivo mouse studies of Sema4D-dependent seizure suppression, and to further the translatability of our findings, we will explore alternative methods of administering Sema4D (e.g. intravenous injection of virus encoding Sema4D) to mice. Lastly, we will test the translatability of our findings with Sema4D in rodents by asking if Sema4D promotes inhibitory synapse formation in human neurons.
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Elucidating the Function of Class 4 Semaphorins in GABAergic Synapse Formation.
  • 批准号:
    9351807
  • 项目类别:
  • 资助金额:
    $2.72万
  • 财政年份:
    2010
  • 负责人:
    SUZANNE PARADIS
  • 依托单位:
Elucidating the Function of Class 4 Semaphorins in GABAergic Synapse Formation
  • 批准号:
    8468221
  • 项目类别:
  • 资助金额:
    $32.51万
  • 财政年份:
    2010
  • 负责人:
    SUZANNE PARADIS
  • 依托单位:
Semaphorin-dependent GABAergic synapse formation: A novel approach to increasing inhibition in the intact brain
  • 批准号:
    10372126
  • 项目类别:
  • 资助金额:
    $57.12万
  • 财政年份:
    2010
  • 负责人:
    SUZANNE PARADIS
  • 依托单位:
Semaphorin-Dependent GABAergic Synapse Formation: A Novel Approach to Increasing Inhibition in the Intact Brain
  • 批准号:
    10609437
  • 项目类别:
  • 资助金额:
    $57.12万
  • 财政年份:
    2010
  • 负责人:
    SUZANNE PARADIS
  • 依托单位:
海外基金