Expressing acid-sensing ion channel 3 in the brain alters acid-evoked currents and impairs fear conditioning.
Expressing acid-sensing ion channel 3 in the brain alters acid-evoked currents and impairs fear conditioning.
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DOI：
10.1111/j.1601-183x.2011.00683.x
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发表时间：
2011-06
期刊：
影响因子：
--
通讯作者：
Wemmie JA
中科院分区：
文献类型：
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作者：
Vralsted VC;Price MP;Du J;Schnizler M;Wunsch AM;Ziemann AE;Welsh MJ;Wemmie JA
先前对编码酸敏感离子通道 1a (ASIC1a) 的基因遭到破坏的小鼠进行的研究表明，ASIC1a 是正常恐惧行为所必需的。为了研究改变大脑 ASIC 亚基组成对行为的影响，我们开发了通过泛神经元突触蛋白 I 启动子表达 ASIC3 的转基因小鼠。这些小鼠在大脑中表达 ASIC3，但未检测到内源性 ASIC3 蛋白。我们发现，在 ASIC3 转基因小鼠中，ASIC3 与内源性 ASIC1a 蛋白共免疫沉淀，并分布在与 ASIC1a 相同的亚细胞脑部分中。此外，ASIC3 显着增加了培养的皮质神经元中酸诱发电流的脱敏率。重要的是，ASIC3 减少了巴甫洛夫恐惧调节对环境和听觉线索的影响。这些观察结果表明 ASIC3 可以与大脑中的 ASIC1a 异源多聚化，并改变内源性通道复合物的生物物理特性。此外，这些数据表明 ASIC 亚基组成和通道脱敏可能是 ASIC 依赖性行为的关键决定因素。
Previous studies on mice with a disruption of the gene encoding acid-sensing ion channel 1a (ASIC1a) suggest that ASIC1a is required for normal fear behavior. To investigate the effects of altering the subunit composition of brain ASICs on behavior, we developed transgenic mice expressing ASIC3 via the pan-neuronal synapsin I promoter. These mice express ASIC3 in the brain, where the endogenous ASIC3 protein is not detected. We found that in ASIC3 transgenic mice, ASIC3 co-immunoprecipitated with the endogenous ASIC1a protein and distributed in the same subcellular brain fractions as ASIC1a. In addition, ASIC3 significantly increased the rate of desensitization of acid-evoked currents in cultured cortical neurons. Importantly, ASIC3 reduced Pavlovian fear conditioning to both context and auditory cues. These observations suggest that ASIC3 can heteromultimerize with ASIC1a in the brain and alter the biophysical properties of the endogenous channel complex. Moreover, these data suggest that ASIC subunit composition and channel desensitization may be critical determinants for ASIC-dependent behavior.