024 - Plasma Exosomal miR-382-5p Modulates Neuroplasticity and Depressive-Like Behaviors in Adolescent Female Rats Exposed to Prenatal Stress

Publication Number: 24.6455

Zhongliang Zhu, Life Science College of Northwest University, XI'AN, Shaanxi, China (People's Republic); Kaixuan Xu, Life Science College of Northwest University, XI'AN, Shaanxi, China (People's Republic); Zhifei Wang, Life Science College of Northwest University, XI'AN, Shaanxi, China (People's Republic); Jinfeng Chen, Life Science College of Northwest University, XI'AN, Shaanxi, China (People's Republic); Hui Li, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi’an, Shaanxi, China (People's Republic)

Background: Prenatal stress (PS) is associated with long-term neurodevelopmental and behavioral issues, including increased depression risk. While boys and girls have similar depression risks pre-puberty, rates in girls nearly double those in boys after puberty onset.

Objective: This study explores the role of plasma-derived exosomes in modulating neuroplasticity and depressive-like behaviors in PS-exposed adolescent female rats, aiming to identify specific exosomal miRNAs involved in these processes.

Design/Methods: Exosomes were isolated from the plasma of PS-induced adolescent female offspring and characterized for exosomal markers. Fluorescently labeled exosomes were intravenously administered to naïve rats, confirming brain uptake, particularly within the dentate gyrus (DG) region. Behavioral impact was assessed using open field, sucrose preference, and forced swim tests. Neurogenesis and synaptic plasticity markers were analyzed in the DG by immunofluorescence and protein assays. miRNA profiling and bioinformatics analyses identified miR-382-5p as a key candidate, whose function and downstream molecular mechanisms were validated both in vitro (in hippocampal neural stem cells and neurons) and in vivo (in the DG of PS-exposed rats).

Results: PS-derived exosomes induced depressive-like behavior in recipient rats, with significant reductions in central zone activity, sucrose preference, and increased immobility in forced swim tests. Reduced neurogenesis was evident with fewer Nestin, Sox2, and Dcx positive cells, and impaired synaptic plasticity was observed, marked by decreased PSD95, Homer1 and dendritic spine density. miRNA profiling analysis showed that miR-382-5p is closely related to synaptic and neurodevelopmental pathways. Functional assays showed that miR-382-5p inhibited the proliferation and differentiation of hippocampal neural stem cells and disrupted synaptic plasticity in neurons. Additionally, in vivo knockdown of its target gene, Slit1, in the DG induced depressive-like behavior and disrupted Wnt/β-catenin signaling pathways involved in neuroplasticity.

Conclusion(s): These findings reveal that exosomal miR-382-5p from PS-induced offspring regulates depressive-like behavior and neuroplasticity through its downstream signaling targets. Modulating these pathways may offer new therapeutic strategies for neuropsychiatric disorders linked to prenatal stress.