CaV 2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures.
CaV 2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures.
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DOI：
10.1002/ana.23913
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发表时间：
2013-08
影响因子：
11.2
通讯作者：
Fishell, Gord
中科院分区：
文献类型：
--
作者：
Rossignol, Elsa;Kruglikov, Illya;van den Maagdenberg, Arn M. J. M.;Rudy, Bernardo;Fishell, Gord
神经元群和机制负责全身性峰波缺失癫痫是知之甚少。在携带编码CaV2.1 （P/ q型）电压门控Ca2+通道α1孔形成亚基的Cacna1a突变的突变小鼠中，普遍的尖峰波发作被认为是由丘脑皮质细胞过度破裂引起的。然而，包括皮质抑制性中间神经元在内的其他细胞群可能有助于这种表型。我们研究了不同的皮质中间神经元亚型如何受到CaV2.1通道功能缺失的影响，以及这如何导致全身性癫痫的发生。我们设计了遗传策略，在小鼠不同皮质gaba能和/或谷氨酸能神经元群中诱导选择性Cacna1a LOF突变。我们通过结合免疫组织化学分析、体外生理学、光遗传学和体内视频脑电图记录来评估这些突变的细胞和网络后果。我们证明，来自皮质中间神经元子集的选择性Cacna1a LOF，包括小白蛋白（PV）和生长抑素（SST）阳性的中间神经元，导致严重的广泛性癫痫。CaV2.1通道功能的缺失会影响PV-而非sst阳性中间神经元的GABA释放。此外，在这些突变体中，丘脑皮质投射神经元没有表现出增强的爆裂，这表明这种特征对全面性尖峰波发作的发展不是必需的。值得注意的是，皮质锥体细胞和中间神经元中CaV2.1通道的同时移除，通过降低皮质兴奋性，显著减轻了癫痫发作的严重程度。我们的研究结果表明，皮质PV中间神经元CaV2.1通道功能的条件消融改变了这些细胞的GABA释放，损害了它们抑制皮质锥体细胞兴奋性的能力，足以引起全身性癫痫发作。
Both the neuronal populations and mechanisms responsible for generalized spike-wave absence seizures are poorly understood. In mutant mice carrying loss-of-function mutations in Cacna1a, which encodes the α1 pore-forming subunit of CaV2.1 (P/Q-type) voltage-gated Ca2+ channels, generalized spike-wave seizures have been suggested to result from excessive bursting of thalamocortical cells. However, other cellular populations including cortical inhibitory interneurons may contribute to this phenotype. We investigated how different cortical interneuron subtypes are affected by the loss of CaV2.1 channel function and how this contributes to the onset of generalized epilepsy. We designed genetic strategies to induce a selective Cacna1a LOF mutation in different cortical GABAergic and/or glutamatergic neuronal populations in mice. We assessed the cellular and network consequences of these mutations by combining immunohistochemical assays, in vitro physiology, optogenetics and in vivo video-EEG recordings. We demonstrate that selective Cacna1a LOF from a subset of cortical interneurons, including parvalbumin (PV)- and somatostatin (SST)-positive interneurons, results in severe generalized epilepsy. Loss of CaV2.1 channel function compromises GABA release from PV-, but not SST-positive interneurons. Moreover, thalamocortical projection neurons do not show enhanced bursting in these mutants, suggesting that this feature is not essential for the development of generalized spike-wave seizures. Notably, the concurrent removal of CaV2.1 channels in cortical pyramidal cells and interneurons considerably lessens seizure severity by decreasing cortical excitability. Our findings demonstrate that conditional ablation of CaV2.1 channel function from cortical PV interneurons alters GABA release from these cells, impairs their ability to constrain cortical pyramidal cell excitability and is sufficient to cause generalized seizures.
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影响因子：
25
作者：
Cruikshank, Scott J.;Lewis, Timothy J.;Connors, Barry W.
通讯作者：
Connors, Barry W.
影响因子：
82.9
作者：
Cope, David W.;Di Giovanni, Giuseppe;Fyson, Sarah J.;Orban, Gergely;Errington, Adam C.;Lorincz, Magor L.;Gould, Timothy M.;Carter, David A.;Crunelli, Vincenzo
通讯作者：
Crunelli, Vincenzo
影响因子：
5.6
作者：
Besag, Frank M. C.
通讯作者：
Besag, Frank M. C.
DOI：
10.1073/pnas.0912204106
发表时间：
2009-12-22
影响因子：
11.1
作者：
Cheong, Eunji;Zheng, Yihong;Shin, Hee-Sup
通讯作者：
Shin, Hee-Sup
影响因子：
5.6
作者：
Engel, Jerome, Jr.
通讯作者：
Engel, Jerome, Jr.