Microcircuits of the Subiculum and Epilepsy

下托和癫痫的微电路

• 批准号: 9789378
• 负责人: Gianmaria MACCAFERRI
• 金额: $ 34.56万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789378
• 关键词: Address; Anatomy; Animal Model; Antiepileptic Agents; Brain; Cells; Chlorides; Computer Simulation; Coupled; Data; Development; Down-Regulation; Epilepsy; Epileptogenesis; Event; Generations; Hippocampus (Brain); Impairment; Interneurons; Knowledge; Membrane Transport Proteins; Molecular; Mus; Neurons; Pharmacology; Play; Population; Pyramidal Cells; Resolution; Role; Series; Signal Transduction; Slice; Synapses; Synaptic plasticity; Techniques; Temporal Lobe Epilepsy; Testing; base; human model; insight; neurochemistry; novel; optogenetics; patch clamp; reconstruction; theories

Project Summary / Abstract A prominent theory regarding the development of epileptic hyper-synchronization in human and animal models of temporal lobe epilepsy proposes a key role for the specific down-regulation of the expression of the KCC2 transporter in subicular pyramidal cells. As KCC2 is essential to maintain the low intracellular chloride concentrations required for hyperpolarizing GABAergic signaling, loss of KCC2 expression would impair GABAergic inhibition and trigger a series of events leading to the emergence of subicular-initiated interictal activity. Furthermore, interictal discharges coupled to synaptic plasticity would result in interictal- ictal transitions and spread hyper-excitability to extra-hippocampal regions. In summary, if the essential aspects of this KCC2-based mechanistic theory of epileptogenesis were correct, the selective pharmacological reduction of KCC2 transporter activity in a naïve subiculum should be sufficient to generate epileptiform activity ranging from interictal-like to, possibly, full ictal-like events. Although this prediction was supported by computational modeling, direct experimental evidence has not yielded definitive results. Our preliminary data show that the application of highly selective KCC2 antagonists on isolated mini-slices of the mouse subiculum generate synchronous interictal-like bursting that depends on depolarizing GABAergic signaling, but are not, apparently, sufficient to trigger ictal-interictal transitions. We will take advantage of a variety of state of the art techniques (simultaneous patch-clamp recordings from synaptically coupled and uncoupled cells, optogenetic control of specific neuronal populations, and high resolution anatomical reconstructions) to investigate the impact of this type of pharmacologically- induced epileptiform activity in subicular mini-slices. We will explore its consequences on intrinsic and synaptic plasticity, reveal the underlying mechanisms played by different interneuron subtypes, and explore whether additional epileptogenic changes and/or synaptic input from extra-subicular regions are necessary to drive interictal-like to ictal-like transitions.

项目摘要 /摘要 关于人和动物中癫痫性超同时化的发展的重要理论 临时叶癫痫提案的模型扮演特定表达表达的特定下调的关键作用 亚锥体细胞中的KCC2转运蛋白。因为KCC2对于维持低细胞内至关重要 过度溶于GABA能信号传导所需的氯化物浓度，KCC2表达的丧失将 损害了GABA能抑制并触发一系列事件，导致下次生引发的出现 临时活动。此外，与突触可塑性耦合的间隔排放将导致充 发射过渡并扩散到高海马区域。 总而言之，如果这种基于KCC2的癫痫发生的机械理论的基本方面是 正确，在幼稚的亚ul的选择性药物减少KCC2转运蛋白活性应应 足以产生癫痫样活性，从充形到可能的，可能的，完全类似的事件。 尽管该预测得到了计算建模的支持，但直接的实验证据尚未 产生了确定的结果。 我们的初步数据表明，高度选择性KCC2拮抗剂在孤立的迷你切片上的应用 小鼠亚致产生的同步间歇性爆发，取决于去极化 GABA能信号传导，但显然不足以触发发作性关系过渡。 我们将利用各种最先进的技术（同时进行补丁钳录制 从突触耦合和未耦合的细胞中，对特定神经元种群的光遗传控制以及 高分辨率的解剖重建），以研究这种类型的药物的影响 诱导下微小切片中的癫痫样活性。我们将探讨它对内在和 突触可塑性，揭示了不同间ron子类型的潜在机制，并且 探索临时区域的其他癫痫发生变化和/或突触输入是否是 要驱动类似ICTAL的过渡所必需的。