Identification of transcriptome alterations in the prefrontal cortex, hippocampus, amygdala and hippocampus of suicide victims

Abstract

Suicide is one of the leading causes of death globally for all ages, and as such presents a very serious problem for clinicians worldwide. However, the underlying neurobiological pathology remains to a large extent unknown. In order to address this gap, we have carried out a genome-wide investigation of the gene expression in the amygdala, hippocampus, prefrontal cortex and thalamus in post-mortem brain samples obtained from 20 suicide completers and 7 control subjects. By KEGG enrichment analysis indicated we identified novel clusters of downregulated pathways involved in antigen neutralization and autoimmune thyroid disease (amygdala, thalamus), decreased axonal plasticity in the hippocampus. Two upregulated pathways were involved in neuronal death in the hippocampus and olfactory transduction in the thalamus and the prefrontal cortex. Autoimmune thyroid disease pathway was downregulated only in females. Metabolic pathways involved in Notch signaling amino acid metabolism and unsaturated lipid synthesis were thalamus-specific. Suicide-associated changes in the expression of several genes and pseudogenes that point to various functional mechanisms possibly implicated in the pathology of suicide. Two genes (SNORA13 and RNU4-2) involved in RNA processing were common to all brain regions analyzed. Most of the identified gene expression changes were related to region-specific dysregulated manifestation of genetic and epigenetic mechanisms underlying neurodevelopmental disorders (SNORD114-10, SUSd1), motivation, addiction and motor disorders (CHRNA6), long-term depression (RAB3B), stress response, major depression and schizophrenia (GFAP), signal transduction at the neurovascular unit (NEXN) and inhibitory neurotransmission in spatial learning, neural plasticity (CALB2; CLIC6, ENPP1). Some of the differentially expressed genes were brain specific non-coding RNAs involved in the regulation of translation (SNORA13). One, (PARM1) is a potential oncogene and prognostic biomarker for colorectal cancer with no known function in the brain. Disturbed gene expression involved in antigen neutralization, autoimmunity, neural plasticity, stress response, signal transduction at the neurovascular unit, dysregulated nuclear RNA processing and translation and epigenetic imprinting signatures is associated with suicide and point to regulatory non-coding RNAs as potential targets of new drugs development.

[Retracted] Helicid Improves Lipopolysaccharide‐Induced Apoptosis of C6 Cells by Regulating SH2D5 DNA Methylation via the CytC/Caspase9/Caspase3 Signaling Pathway

“…Animal and human studies have shown that epigenetic mechanisms can regulate DNA transcription in response to environmental factors and may play a role in the pathological and physiological processes of depression [ 13 ]. Epigenetics refers to changes in expression level of a gene not involving changes in the DNA sequence, such as DNA methylation, histone modification, noncoding RNA, and chromatin remodeling [ 14 ].…”

Microglia as a Hub for Suicide Neuropathology: Future Investigation and Prevention Targets

“…Despite the link between peripheral inflammation and SB ( Figure 1 ), conflicting changes in brain expression of cytokines such as TNF, IL1β, IL6, and IL10 were reported across post-mortem studies of individuals who died by suicide ( Supplementary Table 1 ; Torres-Platas et al, 2014b ; Clark et al, 2016 ; Schiavone et al, 2016 ; Wang et al, 2018 ; Snijders et al, 2020 ). Furthermore, according to gene ontology analysis, the DLPFC, AMY, and TLM of individuals with MDD who died by suicide can present lower expression of gene sets related to microglial immune functions such as “chemokine receptor binding” and “cellular response to LPS” compared to age- and sex-matched individuals with MDD deceased from other causes or healthy controls ( Pantazatos et al, 2017 ; Glavan et al, 2021 ). Such differences could be reconciled by the largely distinct brain regions studied, such as the VLPFC, ACC, and TLM, which likely present diverse baseline inter-individual immune activity, and therefore, a different susceptibility to peripheral inflammation ( Hodes et al, 2014 ; Wood et al, 2015 ).…”

“…A meta-analysis looking at 42 studies published between 1982 and 2019 found a statistically significant but weak influence of sleep disturbances on SB ( Harris et al, 2020 ). Despite the small effect, probably arising from inter-individual variability, lifestyle factors such as sleep are important elements to consider in the complex synergy of microglial features that convey susceptibility to psychiatric disorders ( Picard et al, 2021 ) and SB ( Glavan et al, 2021 ).…”

“…Correspondingly, decreased mRNA Cd11b expression was detected in the ACC of individuals with MDD who died by natural causes but not suicide, compared to age and PMI-matched controls ( Zhang L. et al, 2021 ). Moreover, increased complement protein 3 was detected by microarray in the AMY, HIP, TLM of individuals who died by suicide compared to healthy controls ( Glavan et al, 2021 ). Future studies are needed to explore the role of complement synaptic pruning in SB.…”

“…Further, CD11b-positive cells from MFG, STG, TLM, and SZ tissue presented increased mRNA expression of Cx3cr1 when isolated from individuals with MDD compared to age-matched healthy controls ( Snijders et al, 2020 ). According to a microarray study, increased Cx3cr1 was also detected in the AMY, HIP, and TLM of individuals who died by suicide compared to healthy controls ( Glavan et al, 2021 ). By contrast, no difference in Cx3cr1 mRNA expression was detected in the ACC or DLPFC of individuals with MDD who died by natural causes and suicide, compared to age and PMI-matched controls ( Zhang L. et al, 2021 ).…”