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J Neurosci:小脑钙离子通道功能障碍导致癫痫

来源:生物谷 2013-03-22 21:46

2013年3月20日 讯 /生物谷BIOON/ --近日,一项研究证实小脑神经元中特定的钙通道即所谓的P/Q型信道足以引起功能障碍、不同运动神经元疾病以及一种特殊类型的癫痫。Melanie Mark博士和Stefan Herlitze教授的研究小组的报告结果将有助于开发出特别是针对儿童和年轻的成年人失神癫痫患者的治疗手段。

该研究结果发表在Journal of Neuroscience杂志上。P/Q型通道的缺陷会导致一系列的疾病,在神经生物学领域中主要挑战性问题之一是相关的脑血管疾病。Bochum研究人员回答了这个问题,他致力于解决小脑功能障碍所导致的某些运动障碍。更具体地说,他们研究运动不协调也被称为共济失调,癫痫发作,运动障碍的潜在原因。

在2011年以前的研究中,研究人员发现特定P/Q型钙离子通道是小脑神经元疾病的起源。通道在整个大脑表达,此通道的突变导致偏头痛,癫痫,运动障碍和共济失调的一种不同形式。

令人惊讶的是,我们发现P/Q型通道的损失,特别是在小脑皮质中唯一输出途径Purkinje细胞中损失后,会导致共济失调和运动障碍。因此,该研究小组推测干扰小脑输出信号是足以引起重大疾病表型。换言之,仅小脑P/Q型通道的突变可以引起一系列疾病,即使在其他脑区的相同通道是完整的情况下。

干扰小脑输入信号和干扰输出信号一样,也有类似的效果,Mark团队已发现这一假说的进一步证据。在本研究中,生物学家没有直接干扰Purkinje细胞输出信号,而是这些细胞的输入信号。Purkinje细胞受其他神经元的信号调制,其中包括颗粒细胞。

Purkinje细胞的输入信号对小脑神经元之间适当的通信是重要的,在小鼠实验中,研究人员通过基因改变颗粒细胞的输入信号,使它们不表达P/Q型通道,结果导致共济失调,运动障碍,失神癫痫。

结果还提供了更多的证据表明小脑参与发起和/或神经功能障碍传播,新研究还提供用于识别研究小脑中引发人类疾病的具体途径和分子的动物模型。(生物谷:Bioon.com)

Postnatal Loss of P/Q-Type Channels Confined to Rhombic-Lip-Derived Neurons Alters Synaptic Transmission at the Parallel Fiber to Purkinje Cell Synapse and Replicates Genomic Cacna1a Mutation Phenotype of Ataxia and Seizures in Mice

Takashi Maejima,et al.

Ataxia, episodic dyskinesia, and thalamocortical seizures are associated with an inherited loss of P/Q-type voltage-gated Ca2+ channel function. P/Q-type channels are widely expressed throughout the neuraxis, obscuring identification of the critical networks underlying these complex neurological disorders. We showed recently that the conditional postnatal loss of P/Q-type channels in cerebellar Purkinje cells (PCs) in mice (purky) leads to these aberrant phenotypes, suggesting that intrinsic alteration in PC output is a sufficient pathogenic factor for disease initiation. The question arises whether P/Q-type channel deletion confined to a single upstream cerebellar synapse might induce the pathophysiological abnormality of genomically inherited P/Q-type channel disorders. PCs integrate two excitatory inputs, climbing fibers from inferior olive and parallel fibers (PFs) from granule cells (GCs) that receive mossy fiber (MF) input derived from precerebellar nuclei. In this study, we introduce a new mouse model with a selective knock-out of P/Q-type channels in rhombic-lip-derived neurons including the PF and MF pathways (quirky). We found that in quirky mice, PF-PC synaptic transmission is reduced during low-frequency stimulation. Using focal light stimulation of GCs that express optogenetic light-sensitive channels, channelrhodopsin-2, we found that modulation of PC firing via GC input is reduced in quirky mice. Phenotypic analysis revealed that quirky mice display ataxia, dyskinesia, and absence epilepsy. These results suggest that developmental alteration of patterned input confined to only one of the main afferent cerebellar excitatory synaptic pathways has a significant role in generating the neurological phenotype associated with the global genomic loss of P/Q-type channel function.

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