Dorsal CA1 NECTIN3 Reduction Mediates Early-Life Stress-Induced Object Recognition Memory Deficits in Adolescent Female Mice

• Published in: Neuroscience bulletin
• Main Authors: Ma, Yu-Nu, Zhang, Chen-Chen, Sun, Ya-Xin, Liu, Xiao, Li, Xue-Xin, Wang, Han, Wang, Ting, Wang, Xiao-Dong, Su, Yun-Ai, Li, Ji-Tao, Si, Tian-Mei
• Format: Journal Article
• Language: English
• Published: Singapore 12.10.2024
• Subjects: Early-life stress; Female; Cognition; NECTIN3; Hippocampus
• ISSN: 1673-7067; 1995-8218; 1995-8218
• DOI: 10.1007/s12264-024-01305-z

Early-life stress (ES) leads to cognitive dysfunction in female adolescents, but the underlying neural mechanisms remain elusive. Recent evidence suggests that the cell adhesion molecules NECTIN1 and NECTIN3 play a role in cognition and ES-related cognitive deficits in male rodents. In this study, we aimed to investigate whether and how nectins contribute to ES-induced cognitive dysfunction in female adolescents. Applying the well-established limited bedding and nesting material paradigm, we found that ES impairs recognition memory, suppresses prefrontal NECTIN1 and hippocampal NECTIN3 expression, and upregulates corticotropin-releasing hormone (Crh) and its receptor 1 (Crhr1) mRNA levels in the hippocampus of adolescent female mice. Genetic experiments revealed that the reduction of dorsal CA1 (dCA1) NECTIN3 mediates ES-induced object recognition memory deficits, as knocking down dCA1 NECTIN3 impaired animals' performance in the novel object recognition task, while overexpression of dCA1 NECTIN3 successfully reversed the ES-induced deficits. Notably, prefrontal NECTIN1 knockdown did not result in significant cognitive impairments. Furthermore, acute systemic administration of antalarmin, a CRHR1 antagonist, upregulated hippocampal NECTIN3 levels and rescued object and spatial memory deficits in stressed mice. Our findings underscore the critical role of dCA1 NECTIN3 in mediating ES-induced object recognition memory deficits in adolescent female mice, highlighting it as a potential therapeutic target for stress-related psychiatric disorders in women.