Department of Gynecology and Obstetrics and Research Center for Molecular Metabolomics, Xiangya Hospital Central South University, Changsha, 410008, China.
Department of Physiology, Navy Medical University, Shanghai, 200433, China.
J Neuroinflammation. 2021 Apr 2;18(1):85. doi: 10.1186/s12974-021-02129-8.
Prenatal synthetic glucocorticoid (sGC) exposure increases the susceptibility to cognitive and affective disorders in postnatal life. We previously demonstrated that prenatal sGC exposure results in an increase in corticotropin-releasing hormone (CRH) receptor type 1 (CRHR1) expression in the hippocampus of rats, and CRHR1 is involved in synapse formation via regulation of C-X-C chemokine ligand 5 (CXCL5) in hippocampus. We sought to investigate that the roles of CRHR1 and CXCL5 in learning and memory impairment caused by prenatal sGC exposure.
Pregnant rats were administered with saline or dexamethasone (DEX) from gestational day (GD) 14 to GD21. DEX offspring at 2-day old were treated with saline and CRHR1 antagonists (antalarmin and CP154526) for 7 days. Some DEX offspring received intra-hippocampal injection of AAV9 carrying CXCL5 gene. Spatial learning and memory was assessed by Morris water maze test. Immunofluorescence analysis was applied to show synapsin I and PSD95 signals in hippocampus. Synapsin I and PSD95 protein level and CXCL5 concentration were determined by western blotting and ELISA, respectively. Organotypic hippocampal slice cultures were used to investigate the effect of DEX on CXCL5 production in vitro.
Both male and female DEX offspring displayed impairment of spatial learning and memory in adulthood. Synapsin I and PSD95 signals and CXCL5 levels were decreased in DEX offspring. DEX offspring with antalarmin and CP154526 treatment showed improved spatial learning and memory. Antalarmin and CP154526 treatment increased synapsin I and PSD95 signals and CXCL5 concentration in hippocampus. Bilaterally hippocampal injection of AAV9 carrying CXCL5 gene improved the spatial learning and memory and increased CXCL5 concentration and synapsin I and PSD95 levels in hippocampus. DEX dose-dependently suppressed CXCL5 production in cultured hippocammpal slices, which was prevented by antalarmin treatment.
CRHR1 and CXCL5 signaling in the hippocampus are involved in spatial learning and memory deficits caused by prenatal DEX exposure. CRHR1 activation contributes to decreased CXCL5 production in hippocampus induced by prenatal DEX treatment. Our study provides a molecular basis of prenatal GC exposure programming spatial learning and memory.
产前合成糖皮质激素（sGC）暴露会增加产后认知和情感障碍的易感性。我们之前的研究表明，产前 sGC 暴露会导致大鼠海马中促肾上腺皮质激素释放激素（CRH）受体 1（CRHR1）表达增加，而 CRHR1 通过调节海马中的 C-X-C 趋化因子配体 5（CXCL5）参与突触形成。我们试图研究 CRHR1 和 CXCL5 在产前 sGC 暴露引起的学习和记忆障碍中的作用。
从妊娠第 14 天（GD）到第 21 天（GD），给怀孕的大鼠注射生理盐水或地塞米松（DEX）。2 天大的 DEX 后代用生理盐水和 CRHR1 拮抗剂（antalarmin 和 CP154526）处理 7 天。一些 DEX 后代接受了携带 CXCL5 基因的 AAV9 的海马内注射。空间学习和记忆通过 Morris 水迷宫测试进行评估。免疫荧光分析用于显示海马中的突触素 I 和 PSD95 信号。通过 Western blot 和 ELISA 分别测定突触素 I 和 PSD95 蛋白水平和 CXCL5 浓度。体外使用器官型海马切片培养物研究 DEX 对 CXCL5 产生的影响。
雄性和雌性 DEX 后代在成年期均表现出空间学习和记忆障碍。DEX 后代的突触素 I 和 PSD95 信号和 CXCL5 水平降低。用 antalarmin 和 CP154526 处理的 DEX 后代表现出空间学习和记忆的改善。Antalarmin 和 CP154526 处理增加了海马中的突触素 I 和 PSD95 信号和 CXCL5 浓度。双侧海马注射携带 CXCL5 基因的 AAV9 改善了空间学习和记忆，并增加了海马中的 CXCL5 浓度以及突触素 I 和 PSD95 水平。DEX 呈剂量依赖性地抑制培养海马切片中的 CXCL5 产生，而 antalarmin 处理可预防这种抑制作用。
海马中的 CRHR1 和 CXCL5 信号参与了产前 DEX 暴露引起的空间学习和记忆缺陷。CRHR1 激活导致产前 DEX 处理诱导的海马中 CXCL5 产生减少。我们的研究为产前 GC 暴露编程空间学习和记忆提供了分子基础。
