Frequent spontaneous seizures followed by spatial working memory/anxiety deficits in mice lacking sphingosine 1-phosphate receptor 2
Frequent spontaneous seizures followed by spatial working memory/anxiety deficits in mice lacking sphingosine 1-phosphate receptor 2
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DOI：
10.1016/j.yebeh.2011.09.002
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发表时间：
2011-12-01
影响因子：
2.6
通讯作者：
Ishii, Isao
中科院分区：
文献类型：
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作者：
Akahoshi, Noriyuki;Ishizaki, Yasuki;Ishii, Isao
1-磷酸鞘氨醇 (S1P) 的多种生理作用主要由其 5 个同源 G 蛋白偶联受体介导。 S1P(1)-S1P(5)作为未来的药物靶点而备受关注。为了深入了解 S1P(2) 介导的信号传导，我们分析了与 C57BL/6N 背景多次回交后获得的 S1P(2) 缺陷型 (S1P(2)(-/-)) 小鼠的频繁自发性癫痫发作。对 120 只 S1P(2)(-/-) 小鼠的全时视频记录显示，在出生后第 25 天至第 45 天期间，昼夜有 420 次癫痫发作，伴随着高压同步皮质放电和一系列典型发作：狂奔、强直阵挛性惊厥、冻结，以及偶尔的死亡。 224只S1P(2)(-/-)小鼠中近40%在癫痫发作后死亡，而其余60%的小鼠存活至成年；然而，大约一半的 S1P(2)(-/-) 怀孕小鼠的分娩导致新生死亡。原位杂交揭示了野生型小鼠海马锥体/颗粒神经元中唯一的 s1p(2) 表达，免疫组织化学/微阵列分析发现易癫痫发作的成年 S1P(2)(-/-) 小鼠的整个海马及其邻近新皮质中的神经胶质增生增强。易癫痫发作的成年S1P(2)(-/-)小鼠在八臂径向迷宫测试中表现出空间工作记忆受损，在高架十字迷宫测试中表现出焦虑增加，而它们在逐步测试和海马长时程增强中的被动回避学习记忆表现与野生型小鼠没有区别。我们的研究结果表明，阻断 S1P(2) 信号传导可能会导致癫痫/海马损伤并损害某些特定的中枢神经系统功能。 (C) 2011 Elsevier Inc. 保留所有权利。
The diverse physiological effects of sphingosine 1-phosphate (S1P) are mostly mediated by its five cognate G protein-coupled receptors. S1P(1)-S1P(5), which have attracted much attention as future drug targets. To gain insight into S1P(2)-mediated signaling, we analyzed frequent spontaneous seizures in S1P(2)-deficient (S1P(2)(-/-)) mice obtained after several backcrosses onto a C57BL/6N background. Full-time video recording of 120 S1P(2)(-/-) mice identified 420 seizures both day and night between postnatal days 25 and 45, which were accompanied by high-voltage synchronized cortical discharges and a series of typical episodes: wild run, tonic-clonic convulsion, freezing, and, occasionally, death. Nearly 40% of 224 S1P(2)(-/-) mice died after such seizures, while the remaining 60% of the mice survived to adulthood; however, approximately half of the deliveries from S1P(2)(-/-) pregnant mice resulted in neonatal death. In situ hybridization revealed exclusive s1p(2) expression in the hippocampal pyramidal/granular neurons of wild-type mice, and immunohistochemistry/microarray analyses identified enhanced gliosis in the whole hippocampus and its neighboring neocortex in seizure-prone adult S1P(2)(-/-) mice. Seizure-prone adult S1P(2)(-/-) mice displayed impaired spatial working memory in the eight-arm radial maze test and increased anxiety in the elevated plus maze test, whereas their passive avoidance learning memory performance in the step-through test and hippocampal long-term potentiation was indistinguishable from that of wild-type mice. Our findings suggest that blockade of S1P(2) signaling may cause seizures/hippocampal insults and impair some specific central nervous system functions. (C) 2011 Elsevier Inc. All rights reserved.