Putative role of glial cells in treatment resistance depression: An updated critical literation review and evaluation of single-nuclei transcriptomics data

Author(s)

Sanadgol, Nima ; Feriz, Adib Miraki ; Lisboa, Sabrina F. ; Joca, Samia R. L.

• Document type: Journal article
• Source: Life Sciences; v. 331, p. 12-pg., 2023-08-28.

Abstract

Aims: Major depressive disorder (MDD) is a prevalent global mental illness with diverse underlying causes. Despite the availability of first-line antidepressants, approximately 10-30 % of MDD patients do not respond to these medications, falling into the category of treatment-resistant depression (TRD). Our study aimed to elucidate the precise molecular mechanisms through which glial cells contribute to depression-like episodes in TRD.Materials and methods: We conducted a comprehensive literature search using the PubMed and Scopus electronic databases with search terms carefully selected to be specific to our topic. We strictly followed inclusion and exclusion criteria during the article selection process, adhering to PRISMA guidelines. Additionally, we carried out an in-depth analysis of postmortem brain tissue obtained from patients with TRD using single-nucleus transcriptomics (sn-RNAseq).Key findings: Our data confirmed the involvement of multiple glia-specific markers (25 genes) associated with TRD. These differentially expressed genes (DEGs) primarily regulate cytokine signaling, and they are enriched in important pathways such as NF & kappa;B and TNF-& alpha;. Notably, DEGs showed significant interactions with the transcription factor CREB1. sn-RNAseq analysis confirmed dysregulation of nearly all designated DEGs; however, only Cx30/43, AQP4, S100 & beta;, and TNF-& alpha;R1 were significantly downregulated in oligodendrocytes (OLGs) of TRD patients. With further exploration, we identified the GLT-1 in OLGs as a hub gene involved in TRD.Significance: Our findings suggest that glial dysregulation may hinder the effectiveness of existing therapies for TRD. By targeting specific glial-based genes, we could develop novel interventions with minimal adverse side effects, providing new hope for TRD patients who currently experience limited benefits from invasive treatments. (AU)

• FAPESP's process: 17/24304-0 - New perspectives in the use of drugs that modify atypical neurotransmitters in the treatment of neuropsychiatric disorders
• Grantee: Francisco Silveira Guimaraes
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/24140-0 - Evaluation of P2X7-induced inflammasome activation and microglia M1/M2 polarization in an animal model of treatment-resistant depression
• Grantee: Nima Sanadgol
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/19731-6 - Identification of epigenetic mechanisms induced by stress which modulate endocannabinoid signaling and neuroimmunological mechanisms as new therapeutic targets to treat the posttraumatic stress disorder (PTSD)
• Grantee: Sabrina Francesca de Souza Lisboa
• Support Opportunities: Research Grants - Young Investigators Grants