Elevated NEGR1 in brain induces anxiety or depression-like phenotypes and synaptic dysfunction by Ya-Qi Zhang & Qing Zhang & Yi Yang & Li-Li Yu & Ning-Lin Fan & Yong Wu & Jun-Yang Wang & Xing-Lun Dang & Ying-Qi Guo & Cong Li & Guo-Lan Ma & Lu Wang & Yong-Bo Guo & Shi-Wu Li instant download

Elevated NEGR1 in brain induces anxiety or depression-like phenotypes and synaptic dysfunction by Ya-Qi Zhang & Qing Zhang & Yi Yang & Li-Li Yu & Ning-Lin Fan & Yong Wu & Jun-Yang Wang & Xing-Lun Dang & Ying-Qi Guo & Cong Li & Guo-Lan Ma & Lu Wang & Yong-Bo Guo & Shi-Wu Li instant download

Single nucleotide polymorphisms (SNPs) within 1p31.1 region have shown significant associations with depression, and our priorfunctional genomics pinpointed a regulatory variant rs3101339 among them. However, its precise role in depression pathogenesisremains elusive. In this study, we employed a series of analytical and functional approaches, including regulatory elementannotation, brain expression quantitative trait loci (eQTL), reporter gene assay, electrophoretic mobility shift assay (EMSA), andprecise genome editing. Our results confirmed that rs3101339 is a causal variant within 1p31.1 with its risk allele C upregulatingNEGR1 expression. To further investigate the consequences of NEGR1 upregulation, we overexpressed NEGR1 in specific region ofthe mouse brain (including medial prefrontal cortex (mPFC) and ventral hippocampus (vHIP)) using stereotaxic injection. Behavioral1234567890();,:assessments revealed that elevated NEGR1 levels in the brain, particularly in the vHIP, resulted in working memory impairment aswell as anxiety- and depression-like behaviors in mice. Neuronal sparse labeling assay and transmission electron microscopyrevealed that NEGR1 overexpressing in the vHIP leads to dendritic spine loss and synaptic ultrastructure abnormality.Immunoprecipitation-mass spectrometry (IP-MS) further identified 67 high-confidence proteins that interacted with NEGR1, manyof which are involved in neurotransmitter exocytosis and synaptic vesicle endocytosis. Transcriptomic profiling revealed 94differentially expressed genes in NEGR1-OE (vHIP) mice compared to control mice (P adj < 0.05), which were enriched inmyelination-related signaling pathways (such as myelination, ensheathment of neurons, axon ensheathment in central nervoussystem, etc.). Together, our findings implicated that the overexpression of the NEGR1 gene in the mouse brain as a potential driverof anxiety- or depression-like phenotypes potentially through impairing synaptic function and myelination.Molecular Psychiatry;