Molecular pathology associated with altered synaptic transcriptome in the dorsolateral prefrontal cortex of depressed subjects

Abstract

Disrupted synaptic plasticity is the hallmark of major depressive disorder (MDD), with accompanying changes at the molecular and cellular levels. Often, the maladaptive molecular changes at the synapse are the result of global transcriptional reprogramming dictated by activity-dependent synaptic modulation. Thus far, no study has directly studied the transcriptome-wide expression changes locally at the synapse in MDD brain. Here, we have examined altered synaptic transcriptomics and their functional relevance in MDD with a focus on the dorsolateral prefrontal cortex (dlPFC). RNA was isolated from total fraction and purified synaptosomes of dlPFC from well-matched 15 non-psychiatric controls and 15 MDD subjects. Transcriptomic changes in synaptic and total fractions were detected by next-generation RNA-sequencing (NGS) and analyzed independently. The ratio of synaptic/total fraction was estimated to evaluate a shift in gene expression ratio in MDD subjects. Bioinformatics and network analyses were used to determine the biological relevance of transcriptomic changes in both total and synaptic fractions based on gene–gene network, gene ontology (GO), and pathway prediction algorithms. A total of 14,005 genes were detected in total fraction. A total of 104 genes were differentially regulated (73 upregulated and 31 downregulated) in MDD group based on 1.3-fold change threshold and p < 0.05 criteria. In synaptosomes, out of 13,236 detectable genes, 234 were upregulated and 60 were downregulated (>1.3-fold, p < 0.05). Several of these altered genes were validated independently by a quantitative polymerase chain reaction (qPCR). GO revealed an association with immune system processes and cell death. Moreover, a cluster of genes belonged to the nervous system development, and psychological disorders were discovered using gene–gene network analysis. The ratio of synaptic/total fraction showed a shift in expression of 119 genes in MDD subjects, which were primarily associated with neuroinflammation, interleukin signaling, and cell death. Our results suggest not only large-scale gene expression changes in synaptosomes, but also a shift in the expression of genes from total to synaptic fractions of dlPFC of MDD subjects with their potential role in immunomodulation and cell death. Our findings provide new insights into the understanding of transcriptomic regulation at the synapse and their possible role in MDD pathogenesis.

M6A RNA Methylation-Based Epitranscriptomic Modifications in Plasticity-Related Genes via miR-124-C/EBPα-FTO-Transcriptional Axis in the Hippocampus of Learned Helplessness Rats

“…Our results are functionally relevant MDD-associated impaired synaptic plasticity involving dynamic changes in gene regulatory networks ( Bristot et al, 2020 ; Yoshino et al, 2021b ). These dynamic changes quickly respond to environmental stimuli ( Lopizzo et al, 2019 ).…”

Corticosterone-mediated regulation and functions of miR-218-5p in rat brain

“…1–2 µg total RNA from each sample was taken for RNA-seq library preparation following the method described previoulsy 24 . Briefly, mRNA was isolated from total RNA with NEBNext Poly(A) mRNA Magnetic Isolation Module.…”

Spatial transcriptomic analysis of the mouse brain following chronic social defeat stress

“…Synaptic dysfunction played an important role in the pathogenesis and development of MDD. [51][52][53] Kang et al revealed the decrease in the expression of synaptic function related genes and the corresponding decrease in the number of synapses in dlPFC of MDD subjects. [53] Our results also show that the synaptic plasticity of SUS mice was defective, as indicated by the significant dysregulation of synaptic plasticity related genes (Arc, Cplx2, Syp, Nrgn, Pmch, Calb2, Syt4) in multiple brain regions in SUS mice (Table S4), which may be due to chronic maladjustment of stress response, loss of synaptic connection and impaired synaptogenesis in these brain regions.…”