Plasma reelin levels were decreased in MDD patients and increased after treatment.

Reelin-ApoER2-NR2A/NR2B signaling might play a vital role in pathological mechanism depression.

Peripheral reelin may be a biological marker of great diagnostic value for MDD.

Reelin in the hippocampus might be more involved in the antidepressant effects of vortioxetine.

Major depressive disorder (MDD) is a devastating mental illness and the leading cause of disability worldwide. Previous studies have suggested that synaptic plasticity in the hippocampus plays an important role in depression pathogenesis. Reelin is expressed mainly in the frontal lobe and hippocampus, and is closely associated with neurodevelopment and synaptic plasticity. However, few studies have investigated its role in MDD combining clinical trials and animal experiments. We show that in a clinical trial, plasma reelin levels decreased in patients with first-episode drug-naïve MDD and increased after treatment; further, plasma reelin levels allowed to distinguish drug-naïve patients with first-episode MDD from healthy individuals. In rats, chronic mild and unpredictable stress led to a decrease in both reelin mRNA and protein levels in the hippocampus, which could be reversed by vortioxetine. Subsequent experiments confirmed that the reelin-ApoER2-NR2A /NR2B pathway regulates hippocampal synaptic plasticity and may be involved in depression or antidepressant responses. Our work contributes to a deeper understanding of MDD pathogenesis and provides new evidence that reelin should be considered a potential therapeutic target for MDD.

Major depressive disorder

Reelin

Synaptic plasticity

NMDAR

Vortioxetine

apolipoprotein E receptor 2

the area under the curve

chronic mild and unpredictable stress

diagnostic and statistical manual of mental disorders 5th edition

enzyme-linked immunosorbent assay

γ -aminobutyric acid

Hamilton Anxiety Scale

Hamilton Depression Scale

N-methyl-D-aspartate receptor

N-methyl-D-aspartate receptor subunit 2A

N-methyl-D-aspartate receptor subunit 2B

major depressive disorder

overall composite score

real-time fluorescence quantitative PCR

receiver operating characteristic curve

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