PMID- 33810797 OWN - NLM STAT- MEDLINE DCOM- 20211117 LR - 20211117 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 18 IP - 1 DP - 2021 Apr 2 TI - Spatial learning and memory deficits induced by prenatal glucocorticoid exposure depend on hippocampal CRHR1 and CXCL5 signaling in rats. PG - 85 LID - 10.1186/s12974-021-02129-8 [doi] LID - 85 AB - BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. FAU - Zheng, You AU - Zheng Y AD - Department of Gynecology and Obstetrics and Research Center for Molecular Metabolomics, Xiangya Hospital Central South University, Changsha, 410008, China. AD - Department of Physiology, Navy Medical University, Shanghai, 200433, China. AD - Laboratory of Cell Engineering, Institute of Biotechnology, Beijing, 100071, China. FAU - Zhang, Yan-Min AU - Zhang YM AD - Department of Physiology, Navy Medical University, Shanghai, 200433, China. AD - School of Kinesiology, Shanghai University of Sport, Shanghai, 200438, China. FAU - Tang, Zheng-Shan AU - Tang ZS AD - Department of Gynecology and Obstetrics and Research Center for Molecular Metabolomics, Xiangya Hospital Central South University, Changsha, 410008, China. AD - National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, 410008, China. FAU - Du, Jian-Kui AU - Du JK AD - Department of Gynecology and Obstetrics and Research Center for Molecular Metabolomics, Xiangya Hospital Central South University, Changsha, 410008, China. AD - National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, 410008, China. FAU - Guo, De-Wei AU - Guo DW AD - Department of Gynecology and Obstetrics and Research Center for Molecular Metabolomics, Xiangya Hospital Central South University, Changsha, 410008, China. FAU - Xu, Yong-Jun AU - Xu YJ AD - Department of Physiology, Navy Medical University, Shanghai, 200433, China. FAU - Sheng, Hui AU - Sheng H AD - Department of Physiology, Navy Medical University, Shanghai, 200433, China. FAU - Lu, Jian-Qiang AU - Lu JQ AD - School of Kinesiology, Shanghai University of Sport, Shanghai, 200438, China. FAU - Ni, Xin AU - Ni X AUID- ORCID: 0000-0002-1565-327X AD - Department of Gynecology and Obstetrics and Research Center for Molecular Metabolomics, Xiangya Hospital Central South University, Changsha, 410008, China. xinni2018@csu.edu.cn. AD - Department of Physiology, Navy Medical University, Shanghai, 200433, China. xinni2018@csu.edu.cn. AD - National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, 410008, China. xinni2018@csu.edu.cn. LA - eng GR - 2017YFC1001404/Key Technologies Research and Development Program/ GR - 2018yfc1002802/Key Technologies Research and Development Program/ GR - 81620108013/Major International Joint Research Programme/ GR - 31971102/National Natural Science Foundation of China/ GR - 1814090300/Science and Technology Commission of Shanghai Municipality/ GR - 2018RS3030/Hunan Provincial Science and Technology Department/ PT - Journal Article DEP - 20210402 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (Chemokine CXCL5) RN - 0 (Glucocorticoids) RN - 0 (Receptors, Corticotropin-Releasing Hormone) RN - 5CLY6W2H1M (CRF receptor type 1) RN - 7S5I7G3JQL (Dexamethasone) SB - IM MH - Animals MH - Chemokine CXCL5/antagonists & inhibitors/*metabolism MH - Dexamethasone/toxicity MH - Dose-Response Relationship, Drug MH - Female MH - Glucocorticoids/*toxicity MH - Hippocampus/drug effects/*metabolism MH - Male MH - Maze Learning/drug effects/physiology MH - Memory Disorders/chemically induced/*metabolism MH - Organ Culture Techniques MH - Pregnancy MH - Prenatal Exposure Delayed Effects/chemically induced/*metabolism/psychology MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors/*metabolism MH - Signal Transduction/drug effects/physiology MH - Spatial Learning/drug effects/*physiology PMC - PMC8019183 OTO - NOTNLM OT - CXCL5 OT - Corticotropin-releasing hormone OT - Glucocorticoids OT - Pregnancy OT - Programming OT - Spatial learning and memory COIS- The authors declare no conflicts of interest. EDAT- 2021/04/04 06:00 MHDA- 2021/11/18 06:00 PMCR- 2021/04/02 CRDT- 2021/04/03 05:18 PHST- 2020/12/05 00:00 [received] PHST- 2021/03/12 00:00 [accepted] PHST- 2021/04/03 05:18 [entrez] PHST- 2021/04/04 06:00 [pubmed] PHST- 2021/11/18 06:00 [medline] PHST- 2021/04/02 00:00 [pmc-release] AID - 10.1186/s12974-021-02129-8 [pii] AID - 2129 [pii] AID - 10.1186/s12974-021-02129-8 [doi] PST - epublish SO - J Neuroinflammation. 2021 Apr 2;18(1):85. doi: 10.1186/s12974-021-02129-8.