Overexpressing NEGR1 gene in mice brain induces anxiety or depression-like phenotypes and synaptic dysfunction
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ABSTRACT:
PROVIDER: PRJNA1241292 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32840522_1.fastq.gz | Fastqsanger.gz | |||
| SRR32840522_2.fastq.gz | Fastqsanger.gz | |||
| SRR32840523_1.fastq.gz | Fastqsanger.gz | |||
| SRR32840523_2.fastq.gz | Fastqsanger.gz | |||
| SRR32840524_1.fastq.gz | Fastqsanger.gz |
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Project description:Single nucleotide polymorphisms (SNPs) within 1p31.1 region have been identified as significant genetic variations associated with depression, and our prior functional genomics pinpointed a regulatory variant rs3101339 among them. However, its precise roles in depression pathogenesis remains elusive. In this study, we employed series analytical and functional approaches, including regulatory element annotation, brain expression quantitative trait loci (eQTL), reporter gene assay, electrophoretic mobility shift assay (EMSA), and precision gene editing. Our results confirmed that rs3101339 is a causal variant within 1p31.1 with its risk allele C upregulating NEGR1 expression. To further investigate the consequences of NEGR1 upregulation, we overexpressed NEGR1 in specific region of the mouse brain (including medial prefrontal cortex (mPFC) and ventral hippocampus (vHIP)) using stereotaxic injection. Behavioral assessments revealed that elevated NEGR1 levels in the brain, particularly in the vHIP, results in working memory impairing and anxiety- and depression-like behaviors in mice. Neuronal sparse labeling assays and electron microscopy revealed that NEGR1 overexpressing in the vHIP leads to neural spine loss and synaptic ultrastructure abnormality. Immunoprecipitation-mass spectrometry (IP-MS) further identified 67 high-confidence proteins that interact with NEGR1, many of them are involved in neurotransmitter exocytosis and synaptic vesicle endocytosis. Notably, Snap25 emerged as a potential central hub within this protein-protein interaction network. Transcriptomic profiling revealed 94 differentially expressed genes in NEGR1-OE (vHIP) mice compared to control mice (P adj < 0.05). These genes were enriched in myelination-related signaling pathways (such as myelination, ensheathment of neurons, axon ensheathment in central nervous system, etc.). Moreover, several myelination-related genes, such as Itgax, Itgb4, Mag, Mbp, Sox10, Bcas1, Trf, Slc8a3, Myrf, and Plp1, were downregulated in NEGR1-OE (vHIP) mice. Together, our findings implicated that the overexpression of the NEGR1 gene in the mouse brain as a potential driver of anxiety- or depression-like phenotypes potentially through impairing synaptic function and myelination.
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Project description:MAP kinase signaling has been implicated in brain development, long-term memory, and the response to antidepressants. Inducible Braf knockout mice enabled us to unravel a new role of neuronal MAPK signaling for emotional behavior. Braf mice that were induced during adulthood showed normal anxiety but increased depression-like behavior, in accordance with pharmacological findings. In contrast, the inactivation of Braf in the juvenile brain leads to normal depression-like behavior but decreased anxiety in adults. In these mutants we found no alteration of GABAergic neurotransmission but reduced neuronal arborization in the dentate gyrus. Analysis of gene expression in the hippocampus revealed nine downregulated MAPK target genes that represent candidates to cause the mutant phenotype. Our results reveal the differential function of MAPK signaling in juvenile and adult life phases and emphasize the early postnatal period as critical for the determination of anxiety in adults. Moreover, these results validate inducible gene inactivation as new valuable approach, allowing to discriminate between gene function in the adult and the developing postnatal brain.
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Project description:Bipolar disorder is a complex polygenetic disorder that is characterized by recurrent episodes of depression and mania, the heterogeneity of which is likely complicated by epigenetic modifications that remain to be elucidated. Here, we performed transcriptomic analysis of peripheral blood RNA from monozygotic twins discordant for bipolar disorder and identified a bipolar disorder-associated upregulated long non-coding RNA (lncRNA), AP1AR-DT. We observed that overexpression of AP1AR-DT in the mouse medial prefrontal cortex (mPFC) resulted in a reduction of both the total spine density and the spontaneous excitatory postsynaptic current (sEPSC) frequency of mPFC neurons, as well as depressive and anxiety-like behaviors. A combination of the results of brain transcriptome analysis of AP1AR-DT overexpressing mice brains with the known genes associated with bipolar disorder revealed that NEGR1, which encodes neuronal growth regulator 1, is one of the AP1AR-DT targets and is reduced in vivo upon gain of AP1AR-DT in mice. The results of the present study demonstrated that overexpression of recombinant Negr1 in the mPFC neurons of AP1AR-DTOE mice ameliorates depressive and anxiety-like behaviors and normalizes the reduced excitatory synaptic transmission induced by the gain of AP1AR-DT. Furthermore, the study provides evidence that AP1AR-DT reduces NEGR1 expression by competing for the transcriptional activator NRF1 in the overlapping binding site of the NEGR1 promoter region. The epigenetic and pathophysiological mechanism linking AP1AR-DT to the modulation of excitatory synaptic function provides etiological implications for bipolar disorder.
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