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

Autor(es)

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

• Tipo de documento: Artigo Científico
• Fonte: Life Sciences; v. 331, p. 12-pg., 2023-08-28.

Resumo

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)

• Processo FAPESP: 17/24304-0 - Novas perspectivas no emprego de fármacos que modificam neurotransmissores atípicos no tratamento de transtornos neuropsiquiátricos
• Beneficiário: Francisco Silveira Guimaraes
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 18/24140-0 - Participação da via P2X7-inflamassoma e polarização M1-M2 da micróglia em modelo animal de resistência ao tratamento antidepressivo.
• Beneficiário: Nima Sanadgol
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 17/19731-6 - Identificação de mecanismos epigenéticos induzidos por estresse que modulam a sinalização endocanabinóide e a resposta neuroimunológica como novos alvos farmacológicos no tratamento do transtorno de estresse pós-traumático (PTSD)
• Beneficiário: Sabrina Francesca de Souza Lisboa
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores