外泌体lncRNA DLX6-AS1介导的海马神经元损伤在青少年抑郁症中的作用和机制研究

青少年抑郁症严重危害青少年身心健康，其机制不清。研究报道外泌体与主要精神疾病相关，但其是否与青少年抑郁相关尚不清楚。我们前期发现外泌体可损伤海马神经元，导致青幼期小鼠出现抑郁行为；转录组测序发现青少年抑郁患者外泌体lncRNA DLX6-AS1异常表达，并与临床特征相关；数据库预测提示DLX6-AS1与ERBB4均可结合miR-146b-5p，现有研究报道miR-146b-5p和ERBB4均与抑郁有关；预实验进一步发现miR-146b-5p可抑制靶基因ERBB4表达，该效应能被DLX6-AS1所削弱。因此推测外泌体DLX6-AS1进入海马神经元结合miR-146b-5p，进而调控ERBB4表达引起海马神经元损伤，导致青少年抑郁。本研究拟证明外泌体信号传递在青少年抑郁中的作用，阐明DLX6-AS1介导海马神经元损伤导致青少年抑郁的机制。为青少年抑郁症脑分子机制研究及临床诊疗提供新途径和靶点。

Depression in adolescents can have a serious impact on the physical and mental health of individuals yet its pathogenesis remains to be fully elucidated. Studies have shown that exosomes are associated with major mental disorders yet the role of exosomes in adolescent depression is unclear. Our initial studies showed that exosomes can damage hippocampal neurons and cause depressive behavior in young mice that closely resembling the clinical symptoms in humans. Transcriptome sequencing showed the abnormal expression of exosomal lncRNA DLX6-AS1 in adolescent patients with depression and these changes correlated with the clinical characteristics of patients. Database predictions showed that both DLX6-AS1 and ERBB4 could bind to miR-146b-5p. However, existing studies have reported that both miR-146b-5p and ERBB4 are related to depression. Preliminary experimental showed that miR-146b-5p could inhibit the expression of the target gene ERBB4 and that this effect could be weakened by DLX6-AS1. Therefore, we predict that exosomal DLX6-AS1 enters the hippocampal neurons and binds miR-146b-5p to regulate the expression of the target gene, ERBB4. ERBB4 damages hippocampal neurons and promotes adolescent depression. This study aimed to demonstrate the role of exosomal signaling in adolescent depression and to clarify the mechanism of DLX6-AS1-mediated hippocampal neuron injury that causes adolescent depression. Our results provide new approaches and identify novel targets to study the molecular mechanisms and clinical treatments of depression in adolescent patients.