Elevated NEGR1 in brain induces anxiety or depression-like phenotypes and synaptic dysfunction.

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Single nucleotide polymorphisms (SNPs) in the 1p31.1 region are associated with depression.
• A specific regulatory variant, rs3101339, was previously identified but its role in depression pathogenesis was unclear.

Purpose of the Study:

• To elucidate the precise role of the rs3101339 variant in depression.
• To investigate the functional consequences of NEGR1 gene upregulation in the brain.

Main Methods:

• Regulatory element annotation, brain expression quantitative trait loci (eQTL) analysis.
• Reporter gene assays, electrophoretic mobility shift assay (EMSA), and genome editing.
• Stereotaxic injection for NEGR1 overexpression in mouse brain regions (mPFC, vHIP), behavioral tests, neuronal labeling, electron microscopy, immunoprecipitation-mass spectrometry (IP-MS), and transcriptomic profiling.

Main Results:

• The rs3101339 risk allele C upregulates NEGR1 expression, confirming it as a causal variant.
• NEGR1 overexpression in the mouse ventral hippocampus (vHIP) induced anxiety, depression-like behaviors, and working memory deficits.
• NEGR1 overexpression led to dendritic spine loss, synaptic abnormalities, and altered protein interactions, impacting neurotransmitter exocytosis and vesicle endocytosis.
• Transcriptomic analysis revealed enrichment of myelination-related pathways in NEGR1-overexpressing mice.

Conclusions:

• NEGR1 upregulation in the brain is implicated as a driver of anxiety and depression-like phenotypes.
• Impaired synaptic function and myelination are potential mechanisms underlying these behaviors.
• The rs3101339 variant's role in NEGR1 regulation offers a potential target for understanding and treating depression.