Expression of SV2 isoforms during rodent brain development.
Expression of SV2 isoforms during rodent brain development.
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DOI：
10.1186/1471-2202-14-87
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发表时间：
2013-08-09
期刊：
影响因子：
2.4
通讯作者：
Rogister B
中科院分区：
文献类型：
--
作者：
Crèvecœur J;Foerch P;Doupagne M;Thielen C;Vandenplas C;Moonen G;Deprez M;Rogister B
SV2A、SV2B和SV2C是结构上与主要促进剂超家族(MFS)成员结构相关的突触囊泡蛋白。SV2蛋白的功能和转运底物尚不清楚，尽管它们与突触前钙浓度依赖的神经递质释放有关。SV2A和SV2B在中枢神经系统中广泛表达，而SV2C在纹状体等特定区域的表达更为有限。SV2A基因敲除小鼠在发育后期，大约在出生后第7天(P7)开始出现全身性癫痫发作，并在P15左右死亡。最近，SV2A被证明是批准的抗癫痫药物左乙拉西坦的分子靶点。本工作的目的是精确分析和量化SV2A、SV2B和SV2C在脑发育过程中的表达，以了解这些蛋白在脑发育中的贡献及其对癫痫发作的影响。首先，我们用免疫组织化学的方法系统地分析了小鼠脑发育过程中SV2A、SV2B和SV2C在胚胎第12天(E12)到P30的表达。这一半定量方法表明，在P7左右的海马区，SV2A和SV2B的表达发生了调节。这就是为什么我们使用了各种定量方法(激光显微解剖整个海马区，然后进行qRT-PCR和蛋白质印迹分析)，表明SV2A和SV2B的表达在P5到P7之间增加，而在P7到P10之间保持稳定。此外，在P7时，SV2A在海马区的表达增加，主要在CA1区，而SV2B在该区域的表达保持稳定。观察到的海马区Sv2a表达的变化与Sv2A型−/−动物出生后早期癫痫发作的表现一致，并支持Sv2A型缺失有利于P7前后癫痫发作的假说。
SV2A, SV2B and SV2C are synaptic vesicle proteins that are structurally related to members of the major facilitator superfamily (MFS). The function and transported substrate of the SV2 proteins is not clearly defined although they are linked to neurotransmitters release in a presynaptic calcium concentration-dependent manner. SV2A and SV2B exhibit broad expression in the central nervous system while SV2C appears to be more restricted in defined areas such as striatum. SV2A knockout mice start to display generalized seizures at a late developmental stage, around post-natal day 7 (P7), and die around P15. More recently, SV2A was demonstrated to be the molecular target of levetiracetam, an approved anti-epileptic drug (AED). The purpose of this work was to precisely analyze and quantify the SV2A, SV2B and SV2C expression during brain development to understand the contribution of these proteins in brain development and their impact on epileptic seizures. First, we systematically analyzed by immunohistofluorescence, the SV2A, SV2B and SV2C expression during mouse brain development, from embryonic day 12 (E12) to P30. This semi-quantitative approach suggests a modulation of SV2A and SV2B expression in hippocampus around P7. This is the reason why we used various quantitative approaches (laser microdissection of whole hippocampus followed by qRT-PCR and western blot analysis) indicating that SV2A and SV2B expression increased between P5 and P7 and remained stable between P7 and P10. Moreover, the increase of SV2A expression in the hippocampus at P7 was mainly observed in the CA1 region while SV2B expression in this region remains stable. The observed alterations of SV2A expression in hippocampus are consistent with the appearance of seizures in SV2A−/− animals at early postnatal age and the hypothesis that SV2A absence favors epileptic seizures around P7.
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