Downregulated NPAS4 in multiple brain regions is associated with Major Depressive Disorder

Abstract

Major Depressive Disorder (MDD) is a commonly observed psychiatric disorder that affects more than 2% of the world population with a rising trend. However, disease-associated pathways and biomarkers are yet to be fully comprehended. In this study, we analyzed previously generated RNA-seq data across seven different brain regions from three distinct studies to identify differentially and co-expressed genes for patients with MDD. Differential gene expression (DGE) analysis revealed that NPAS4 is the only gene downregulated in three different brain regions. Furthermore, co-expressing gene modules responsible for glutamatergic signaling are negatively enriched in these regions. We used the results of both DGE and co-expression analyses to construct a novel MDD-associated pathway. In our model, we propose that disruption in glutamatergic signaling-related pathways might be associated with the downregulation of NPAS4 and many other immediate-early genes (IEGs) that control synaptic plasticity. In addition to DGE analysis, we identified the relative importance of KEGG pathways in discriminating MDD phenotype using a machine learning-based approach. We anticipate that our study will open doors to developing better therapeutic approaches targeting glutamatergic receptors in the treatment of MDD.

Endocannabinoid and neuroplasticity-related changes as susceptibility factors in a rat model of posttraumatic stress disorder

“…Indeed. Npas4 downregulation in several brain regions in the fear circuitry was shown to be associated with stress-related psychopathologies 37 . Decreased expression of Arc, another immediate early gene that similarly to Npas4 showed downregulation in our model, was shown to specifically increase susceptibility to trauma-induced adverse behavioral changes 36 .…”

“…expression of several immediate early genes, as markers of neuronal activity 33 , and modulators of neuroplasticity 34 . Expression of such genes directly contributes to fear learning 35 , are involved in stress vulnerability 36 and their expression changes are associated with stress-related mental disorders 37 . Furthermore, they interact with eCB signaling in the modulation of synaptic activity 38 .…”

Cerebellar contribution to cognitive deficits and prefrontal cortex dysfunction in Spinocerebellar Ataxia Type 1 (SCA1)

“…Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified alterations in inflammatory IL17 pathway and amphetamine addiction (Figure 2C). Among the corticosterone pathways genes were Th 39 , Trh 40 and Npas [41][42][43][44] .…”