The dorsal hippocampal CA3 regulates spatial reference memory through the CtBP2/GluR2 pathway
The dorsal hippocampal CA3 regulates spatial reference memory through the CtBP2/GluR2 pathway
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DOI：
10.1096/fj.202101609rr
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发表时间：
2022-09-01
期刊：
影响因子：
4.8
通讯作者：
Lian, Hong
中科院分区：
文献类型：
--
作者：
Han, Jia-Xuan;Wen, Chen-Xi;Lian, Hong
背侧海马在空间记忆中起着关键作用。然而，亚区域特异性分子通路在空间认知中的作用仍不清楚。我们观察到，转录辅助调节C-末端结合蛋白2（CtBP2）提出了CA3特异性富集的表达。CtBP2在背侧CA3（dCA3）神经元中的RNAi干扰，而不是腹侧CA3（vCA3），特异性地损害空间参考记忆，并降低AMPA受体的钙渗透性决定子亚基GluR2的表达。GluR2缺失的钙渗透性AMPA受体拮抗剂的应用挽救了dCA 3 CtBP2敲低动物的空间记忆缺陷。转录组学分析表明CtBP 2可能通过翻译后机制调节GluR2蛋白水平，尤其是通过内吞途径调节AMPA受体分选。一致的是，CtBP2缺陷改变了多个内吞调节基因的mRNA表达，并且在原代海马神经元中CtBP2敲低增强了含GluR2的AMPA受体的内吞。总之，我们的研究结果提供了证据表明，dCA 3调节空间参考记忆的CtBP 2/GluR2途径，通过调节钙渗透AMPA受体。
The dorsal hippocampus plays a pivotal role in spatial memory. However, the role of subregion-specific molecular pathways in spatial cognition remains unclear. We observed that the transcriptional coregulator C-terminal binding protein 2 (CtBP2) presented CA3-specific enrichment in expression. RNAi interference of CtBP2 in the dorsal CA3 (dCA3) neurons, but not the ventral CA3 (vCA3), specifically impaired spatial reference memory and reduced the expression of GluR2, the calcium permeability determinant subunit of AMPA receptors. Application of an antagonist for GluR2-absent calcium permeable AMPA receptors rescued spatial memory deficits in dCA3 CtBP2 knockdown animals. Transcriptomic analysis suggest that CtBP2 may regulate GluR2 protein level through post-translational mechanisms, especially by the endocytosis pathway which regulates AMPA receptor sorting. Consistently, CtBP2 deficiency altered the mRNA expression of multiple endocytosis-regulatory genes, and CtBP2 knockdown in primary hippocampal neurons enhanced GluR2-containing AMPA receptor endocytosis. Together, our results provide evidence that the dCA3 regulates spatial reference memory by the CtBP2/GluR2 pathway through the modulation of calcium permeable AMPA receptors.