Analysis of knock-out mice to determine the role of HPC-1/syntaxin 1A in expressing synaptic plasticity
Analysis of knock-out mice to determine the role of HPC-1/syntaxin 1A in expressing synaptic plasticity
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DOI：
10.1523/jneurosci.0289-06.2006
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发表时间：
2006-05-24
影响因子：
5.3
通讯作者：
Akagawa, Kimio
中科院分区：
文献类型：
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作者：
Fujiwara, Tomonori;Mishima, Tatsuya;Akagawa, Kimio
蛋白HPC-1/syntaxin 1A在神经元中大量表达并定位于神经元质膜。它与SNAP-25（25 kDa突触体相关蛋白）和VAMP-2（囊泡相关膜蛋白）/突触泡蛋白形成称为SNARE（可溶性N-乙基马来酰亚胺敏感融合蛋白附着蛋白受体）复合物的复合物，这被认为是突触囊泡胞吐作用所必需的;因此，HPC-1/突触融合蛋白1A被认为是突触传递的关键。为了研究HPC-1/syntaxin 1A在体内的生理功能，我们通过靶向基因破坏产生敲除（KO）小鼠。虽然HPC-1/syntaxin 1A表达完全耗尽，对其他SNARE蛋白的表达没有任何影响，但KO小鼠是存活的。它们生长正常，可育，与对照同窝仔相比，外观无差异。在体外培养的KO小鼠海马神经元中，基本的突触传递是正常的。然而，突变小鼠海马切片的长时程增强受损。此外，尽管KO小鼠在隐藏平台测试中表现出正常的空间记忆，但条件性恐惧记忆的巩固受损。有趣的是，KO小鼠的条件性恐惧记忆消退受损。这些结果表明，HPC-1/syntaxin 1A可能与突触可塑性密切相关。
The protein HPC-1/syntaxin 1A is abundantly expressed in neurons and localized in the neuronal plasma membrane. It forms a complex with SNAP-25 (25 kDa synaptosomal-associated protein) and VAMP-2 (vesicle-associated membrane protein)/synaptobrevin called SNARE (a soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor) complex, which is considered essential for synaptic vesicle exocytosis; thus, HPC-1/syntaxin 1A is considered crucial for synaptic transmission. To examine the physiological function of HPC-1/syntaxin 1A in vivo, we produced knock-out (KO) mice by targeted gene disruption. Although HPC-1/syntaxin 1A expression was completely depleted without any effect on the expression of other SNARE proteins, the KO mice were viable. They grew normally, were fertile, and displayed no difference in appearance compared with control littermate. In cultured hippocampal neurons derived from the KO mice, the basic synaptic transmission in vitro was normal. However, the mutant mice had impaired long-term potentiation in the hippocampal slice. Also, although KO mice exhibited normal spatial memory in the hidden platform test, consolidation of conditioned fear memory was impaired. Interestingly, the KO mice had impaired conditioned fear memory extinction. These observations suggest that HPC-1/syntaxin 1A may be closely related to synaptic plasticity.