Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Center of Brain Science and Brain-machine Integration, School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, China.
FASEB J. 2022 Sep;36(9):e22456. doi: 10.1096/fj.202101609RR.
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.
背侧海马在空间记忆中起着关键作用。然而，亚区特异性分子途径在空间认知中的作用尚不清楚。我们观察到转录共激活因子 C 端结合蛋白 2（CtBP2）在 CA3 区的表达中具有 CA3 特异性富集。在背侧 CA3（dCA3）神经元中 RNAi 干扰 CtBP2，但不在腹侧 CA3（vCA3）中，特异性地损害了空间参考记忆，并降低了 AMPA 受体的钙通透性决定亚基 GluR2 的表达。GluR2 缺失的钙通透性 AMPA 受体拮抗剂的应用挽救了 dCA3 CtBP2 敲低动物的空间记忆缺陷。转录组分析表明，CtBP2 可能通过翻译后机制调节 GluR2 蛋白水平，特别是通过内吞作用途径调节 AMPA 受体的分拣。一致地，CtBP2 缺失改变了多个内吞作用调节基因的 mRNA 表达，并且原代海马神经元中的 CtBP2 敲低增强了含有 GluR2 的 AMPA 受体内吞作用。总之，我们的结果提供了证据表明，dCA3 通过 CtBP2/GluR2 途径通过调节钙通透性 AMPA 受体来调节空间参考记忆。
