Impairment of Catecholamine Systems during Induction of Long-Term Potentiation at Hippocampal CA1 Synapses in HPC-1/Syntaxin 1A Knock-out Mice
Impairment of Catecholamine Systems during Induction of Long-Term Potentiation at Hippocampal CA1 Synapses in HPC-1/Syntaxin 1A Knock-out Mice
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DOI：
10.1523/jneurosci.2911-11.2012
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发表时间：
2012-01-04
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：
Mishima, Tatsuya;Fujiwara, Tomonori;Akagawa, Kimio
膜蛋白HPC-1/Synaxin 1A被认为在突触囊泡的胞吐中起关键作用，最近被认为是突触可塑性所必需的。尽管有证据表明HPC-1/Synaxin 1A在突触可塑性中的作用，但其潜在的细胞机制尚不清楚。我们发现，尽管快速突触传递和长期抑制没有受到影响，但HPC-1/Synaxin 1A基因敲除(STX1A(-/-))小鼠对CA1海马片的theta-Burst刺激表现出长期增强(LTP)受损。应用腺酰环化酶激活剂Forsklin或更强烈的刺激可以挽救LTP中的损伤，这表明cAMP/蛋白激酶A信号在这些小鼠中受到抑制。此外，STX1A(-/-)小鼠海马儿茶酚胺的释放显著减少。由于HPC-1/Synaxin 1A调节致密核突触小泡的胞吐，其中含有去甲肾上腺素、多巴胺和5-羟色胺等神经调制递质，因此我们研究了神经调制递质在LTP诱导中的作用。去甲肾上腺素和多巴胺增加了STX1A(-/-)小鼠LTP的诱导，而儿茶酚胺的耗竭降低了野生型小鼠的LTP诱导。这些结果表明，HPC-1/Synaxin 1A通过对致密核突触小泡的胞吐来调节儿茶酚胺能系统，而HPC-1/Synaxin 1A的缺失导致LTP诱导功能障碍。
The membrane protein HPC-1/syntaxin 1A is believed to play a key role in synaptic vesicle exocytosis, and it was recently suggested to be required for synaptic plasticity. Despite evidence for the function of HPC-1/syntaxin 1A in synaptic plasticity, the underlying cellular mechanism is unclear. We found that although fast synaptic transmission and long-term depression were unaffected, HPC-1/syntaxin 1A knock-out (STX1A(-/-)) mice showed impaired long-term potentiation (LTP) in response to theta-burst stimulation in CA1 hippocampal slices. The impairment in LTP was rescued by the application of forskolin, an adenylyl cyclase activator, or more robust stimulation, suggesting that cAMP/protein kinase A signaling was suppressed in these mice. In addition, catecholamine release from the hippocampus was significantly reduced in STX1A(-/-) mice. Because HPC-1/syntaxin 1A regulates exocytosis of dense-core synaptic vesicles, which contain neuromodulatory transmitters such as noradrenaline, dopamine and 5-HT, we examined the effect of neuromodulatory transmitters on LTP induction. Noradrenaline and dopamine enhanced LTP induction in STX1A(-/-) mice, whereas catecholamine depletion reduced LTP induction in wild-type mice. Theses results suggest that HPC-1/syntaxin 1A regulates catecholaminergic systems via exocytosis of dense-core synaptic vesicles, and that deletion of HPC-1/syntaxin 1A causes impairment of LTP induction.