Hippocampus-related cognitive disorders develop in the absence of epilepsy and ataxia in the heterozygous Cacna1a mutant mice tottering

IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Akito Nakao, Katsumi Hayashida, H. Ogura, Y. Mori, K. Imoto
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引用次数: 1

Abstract

ABSTRACT CACNA1A-associated epilepsy and ataxia frequently accompany cognitive impairments as devastating co-morbidities. However, it is unclear whether the cognitive deficits are consequences secondary to the neurological symptoms elicited by CACNA1A mutations. To address this issue, Cacna1a mutant mice tottering (tg), and in particular tg/+ heterozygotes, serve as a suitable model system, given that tg/+ heterozygotes fail to display spontaneous absence epilepsy and ataxia typically observed in tg/tg homozygotes. Here, we examined hippocampus-dependent behaviors and hippocampal learning-related synaptic plasticity in tg mice. In behavioral analyses of tg/+ and tg/tg, acquisition and retention of spatial reference memory were characteristically impaired in the Morris water maze task, while working memory was intact in the eight-arm radial maze and T-maze tasks. tg/+ heterozygotes showed normal motor function in contrast to tg/tg homozygotes. In electrophysiological analyses, Schaffer collateral–CA1 synapses showed a deficit in the maintenance of long-term potentiation in tg/+ and tg/tg mice and an increased paired-pulse facilitation induced by paired pulses with 100 ms in tg/tg mice. Our results indicate that the tg mutation causes a dominant disorder of the hippocampus-related memory and synaptic plasticity, raising the possibility that in CACNA1A-associated human diseases, functionally aberrant CaV2.1 Ca2+ channels actively induce the observed cognitive deficits independently of the neurological symptoms.
杂合子Cacna1a突变小鼠在没有癫痫和共济失调的情况下发展海马相关认知障碍
cacna1a相关的癫痫和共济失调经常伴随认知障碍,是毁灭性的合并症。然而,目前尚不清楚认知缺陷是否继发于CACNA1A突变引起的神经系统症状。为了解决这一问题,考虑到tg/+杂合子不能表现出tg/tg纯合子典型的自发性缺失癫痫和共济失调,Cacna1a突变小鼠(tg),特别是tg/+杂合子,可以作为合适的模型系统。在这里,我们研究了tg小鼠的海马依赖行为和海马学习相关的突触可塑性。在tg/+和tg/tg的行为学分析中,Morris水迷宫任务中空间参考记忆的习得和保留出现了明显的损伤,而八臂桡形迷宫和t形迷宫任务中工作记忆的习得和保留是完整的。Tg /+杂合子与Tg / Tg纯合子相比,运动功能正常。电生理分析显示,tg/+和tg/tg小鼠的Schaffer旁支- ca1突触在维持长期增强方面存在缺陷,而tg/tg小鼠的配对脉冲在100 ms时诱导的配对脉冲促进增加。我们的研究结果表明,tg突变导致海马相关记忆和突触可塑性的显性障碍,这提高了在cacna1a相关的人类疾病中,功能异常的CaV2.1 Ca2+通道积极诱导所观察到的独立于神经系统症状的认知缺陷的可能性。
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来源期刊
Channels
Channels 生物-生化与分子生物学
CiteScore
5.90
自引率
0.00%
发文量
21
审稿时长
6-12 weeks
期刊介绍: Channels is an open access journal for all aspects of ion channel research. The journal publishes high quality papers that shed new light on ion channel and ion transporter/exchanger function, structure, biophysics, pharmacology, and regulation in health and disease. Channels welcomes interdisciplinary approaches that address ion channel physiology in areas such as neuroscience, cardiovascular sciences, cancer research, endocrinology, and gastroenterology. Our aim is to foster communication among the ion channel and transporter communities and facilitate the advancement of the field.
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