Key Laboratory of Ethnomedicine of Ministry of Education, Center on Translational Neuroscience, School of Pharmacy, Minzu University of China, Beijing, China.
Section on Cellular Neurobiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.
Transl Psychiatry. 2023 Apr 26;13(1):135. doi: 10.1038/s41398-023-02429-y.
Carboxypeptidase E (CPE) is a multifunctional protein with many nonenzymatic functions in various systems. Previous studies using CPE knock-out mice have shown that CPE has neuroprotective effects against stress and is involved in learning and memory. However, the functions of CPE in neurons are still largely unknown. Here we used a Camk2a-Cre system to conditionally knockout CPE in neurons. The wild-type, CPE, and CPE mice were weaned, ear-tagged, and tail clipped for genotyping at 3 weeks old, and they underwent open field, object recognition, Y-maze, and fear conditioning tests at 8 weeks old. The CPE mice had normal body weight and glucose metabolism. The behavioral tests showed that CPE mice had impaired learning and memory compared with wild-type and CPE mice. Surprisingly, the subiculum (Sub) region of CPE mice was completely degenerated, unlike the CPE full knockout mice, which exhibit CA3 region neurodegeneration. In addition, doublecortin immunostaining suggested that neurogenesis in the dentate gyrus of the hippocampus was significantly reduced in CPE mice. Interestingly, TrkB phosphorylation in the hippocampus was downregulated in CPE mice, but brain-derived neurotrophic factor levels were not. In both the hippocampus and dorsal medial prefrontal cortex, we observed reduced MAP2 and GFAP expression in CPE mice. Taken together, the results of this study demonstrate that specific neuronal CPE knockout leads to central nervous system dysfunction in mice, including learning and memory deficits, hippocampal Sub degeneration and impaired neurogenesis.
羧肽酶 E（CPE）是一种多功能蛋白，在各种系统中具有许多非酶功能。先前使用 CPE 敲除小鼠的研究表明，CPE 具有应激保护作用，并参与学习和记忆。然而，CPE 在神经元中的功能在很大程度上仍然未知。在这里，我们使用 Camk2a-Cre 系统在神经元中条件性敲除 CPE。在 3 周龄时，对野生型、CPE 和 CPE 小鼠进行断乳、耳标和尾夹以进行基因分型，并在 8 周龄时进行旷场、物体识别、Y 迷宫和恐惧条件反射测试。CPE 小鼠的体重和葡萄糖代谢正常。行为测试表明，与野生型和 CPE 小鼠相比，CPE 小鼠的学习和记忆能力受损。令人惊讶的是，CPE 小鼠的 Sub 区完全退化，与 CPE 完全敲除小鼠不同，后者表现出 CA3 区神经退行性变。此外，双皮质素免疫染色表明 CPE 小鼠海马齿状回的神经发生明显减少。有趣的是，CPE 小鼠海马中的 TrkB 磷酸化下调，但脑源性神经营养因子水平没有下调。在海马体和背侧内侧前额叶皮层中，我们观察到 CPE 小鼠中 MAP2 和 GFAP 的表达减少。总之，这项研究的结果表明，特定神经元 CPE 敲除会导致小鼠中枢神经系统功能障碍，包括学习和记忆缺陷、海马 Sub 退化和神经发生受损。
