National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, 100191, China.
Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), and National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, Beijing, 100191, China.
Mol Psychiatry. 2022 May;27(5):2522-2532. doi: 10.1038/s41380-022-01495-w. Epub 2022 Mar 9.
Depression is more prevalent among adolescents than adults, but the underlying mechanisms remain largely unknown. Using a subthreshold chronic stress model, here we show that developmentally regulated expressions of the perineuronal nets (PNNs), and one of the components, Neurocan in the prelimbic cortex (PrL) are important for the vulnerability to stress and depressive-like behaviors in both adolescent and adult rats. Reduction of PNNs or Neurocan with pharmacological or viral methods to mimic the expression of PNNs in the PrL during adolescence compromised resilience to stress in adult rats, while virally mediated overexpression of Neurocan reversed vulnerability to stress in adolescent rats. Ketamine, a recent-approved drug for treatment-resistant depression rescued impaired function of Parvalbumin-positive neurons function, increased expression of PNNs in the PrL, and reversed depressive-like behaviors in adolescent rats. Furthermore, we show that Neurocan mediates the anti-depressant effect of ketamine, virally mediated reduction of Neurocan in the PrL abolished the anti-depressant effect of ketamine in adolescent rats. Our findings show an important role of Neurocan in depression in adolescence, and suggest a novel mechanism for the anti-depressant effect of ketamine.
抑郁症在青少年中的发病率高于成年人，但潜在机制在很大程度上仍不清楚。本研究使用亚阈值慢性应激模型，表明发育期神经周围网（PNNs）的表达及其成分之一神经黏蛋白在成年和青春期大鼠的应激易感性和抑郁样行为中起重要作用。用药理学或病毒方法减少 PNNs 或神经黏蛋白，以模拟青春期 PrL 中 PNNs 的表达，会损害成年大鼠的应激适应能力，而病毒介导的神经黏蛋白过表达则逆转了青春期大鼠对应激的易感性。氯胺酮是一种最近批准用于治疗难治性抑郁症的药物，可恢复 Parvalbumin 阳性神经元功能的损伤，增加 PrL 中 PNNs 的表达，并逆转青春期大鼠的抑郁样行为。此外，我们还表明，神经黏蛋白介导了氯胺酮的抗抑郁作用，在 PrL 中病毒介导的神经黏蛋白减少消除了氯胺酮在青春期大鼠中的抗抑郁作用。本研究结果表明神经黏蛋白在青少年抑郁症中起重要作用，并为氯胺酮的抗抑郁作用提供了新的机制。
