Knockdown of CLC-3 in the hippocampal CA1 impairs contextual fear memory
Knockdown of CLC-3 in the hippocampal CA1 impairs contextual fear memory
复制标题
海马 CA1 区 CLC-3 的敲低会损害情境恐惧记忆
DOI：
10.1016/j.pnpbp.2018.07.004
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发表时间：
2019-03-08
影响因子：
5.6
通讯作者：
Zhao, Hu
中科院分区：
文献类型：
--
作者：
Chen, Ye-Fei;Chen, Zi-Xiang;Zhao, Hu
先前的研究支持海马在情境恐惧记忆中的关键作用。创伤后应激障碍（PTSD）患者海马结构和功能改变频繁发生。最近的报道显示，CLC-3，阴离子通道和转运蛋白的CLC家族的成员，敲除，导致神经元变性和海马的损失。然而，CLC-3在情境恐惧记忆中的作用仍然未知。利用腺病毒和腺相关病毒基因转移技术，敲低海马CA 1区CLC-3基因，研究CLC-3在情境恐惧记忆中的作用。长时程情境恐惧记忆形成后海马CA 1区CLC-3表达增加通过腺病毒输注在海马CA 1区敲低CLC-3显著减弱背景恐惧记忆，降低棘密度，诱导兴奋性突触超微结构的缺陷，表现为PSD长度、PSD厚度和活动区长度的减少，并损害L-LTP的诱导和维持。CLC-3的敲低还诱导突触NMDAR亚基组成为增加的GluN 2A/GluN 2B比率模式并降低CaMK II-α的活性。此外，由CaMK II-α启动子驱动的腺相关病毒选择性地敲低兴奋性神经元中的CLC-3足以损害长期情境恐惧记忆。这些发现强调了海马CA 1区的CLC-3是情境恐惧记忆所必需的。
Previous studies support a critical role of hippocampus in contextual fear memory. Structural and functional alterations of hippocampus occur frequently in posttraumatic stress disorders (PTSD). Recent reports reveal that knockout of CLC-3, a member of the CLC family of anion channels and transporters, leads to neuronal degeneration and loss of hippocampus. However, the role of CLC-3 in contextual fear memory remains unknown. Using adenovirus and adeno-associated virus gene transfer to knockdown CLC-3 in hippocampal CA1, we investigate the role of CLC-3 in contextual fear memory. CLC-3 expression is increased in hippocampal CA1 after formation of long-term contextual fear memory. Knockdown of CLC-3 by adenovirus infusion in hippocampal CA1 significantly attenuates the contextual fear memory, reduces spine density, induces defects of excitatory synaptic ultrastructure showed by the decreased PSD length, PSD thickness and active zone length, and impairs L-LTP induction and maintenance. Knockdown of CLC-3 also induces the synaptic NMDAR subunit composition to an increased GluN2A/GluN2B ratio pattern and reduces the activity of CaMKII-alpha. Furthermore, selectively knockdown of CLC-3 in excitatory neurons by adeno-associated virus driven from CaMKII-alpha promoter is sufficient to impair long-term contextual fear memory. These findings highlight that CLC-3 in hippocampal CA1 is necessary for contextual fear memory.