Carboxypeptidase E conditional knockout mice exhibit learning and memory deficits and neurodegeneration

被引:6
|
作者
Fan, Fang-Cheng [1 ]
Du, Yang [1 ]
Zheng, Wen-Hui [1 ]
Loh, Y. Peng [2 ]
Cheng, Yong [1 ,3 ,4 ]
机构
[1] Minzu Univ China, Ctr Translat Neurosci, Sch Pharm, Key Lab Ethnomedi,Minist Educ, Beijing, Peoples R China
[2] Eunice Kennedy Shriver NICHHD, Sect Cellular Neurobiol, NIH, Bethesda, MD 20892 USA
[3] Minzu Univ China, Coll Life & Environm Sci, Beijing, Peoples R China
[4] Minzu Univ China, Inst Natl Secur, Beijing, Peoples R China
基金
中国国家自然科学基金;
关键词
NEUROTROPHIC FACTOR-ALPHA-1; CHRONIC STRESS; HIPPOCAMPUS; MUTATION; ENDOCRINE; RETRIEVAL; OBESITY; ROLES; BRAIN; LEADS;
D O I
10.1038/s41398-023-02429-y
中图分类号
R749 [精神病学];
学科分类号
100205 ;
摘要
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, CPEflox/-, and CPEflox/flox 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 CPEflox/flox mice had normal body weight and glucose metabolism. The behavioral tests showed that CPEflox/flox mice had impaired learning and memory compared with wild-type and CPEflox/- mice. Surprisingly, the subiculum (Sub) region of CPEflox/flox 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 CPEflox/flox mice. Interestingly, TrkB phosphorylation in the hippocampus was downregulated in CPEflox/flox 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 CPEflox/flox 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.
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页数:9
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