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.
AbstractMajor 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.
KeywordsMajor depressive disorder
Reelin
Synaptic plasticity
NMDAR
Vortioxetine
AbbreviationsApoER2apolipoprotein E receptor 2
AUCthe area under the curve
CUMSchronic mild and unpredictable stress
DSM-5diagnostic and statistical manual of mental disorders 5th edition
ELISAenzyme-linked immunosorbent assay
GABAγ -aminobutyric acid
HAMAHamilton Anxiety Scale
HAMDHamilton Depression Scale
NMDARN-methyl-D-aspartate receptor
NR2AN-methyl-D-aspartate receptor subunit 2A
NR2BN-methyl-D-aspartate receptor subunit 2B
MDDmajor depressive disorder
OCoverall composite score
qPCRreal-time fluorescence quantitative PCR
ROCreceiver operating characteristic curve
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