Interactive neuroinflammation pathways and transcriptomics-based identification of drugs and chemical compounds for schizophrenia

Abstract

Abstract Background Schizophrenia is a psychiatric disorder affecting one percent of the worldwide population. Despite the progress in elucidating its aetiology, treatment strategies have not succeeded in alleviating the symptoms effectively. Accumulating evidence indicates that neuroinflammation is involved in the pathology of these disorders by altering neurodevelopmental processes and specifically affecting glutamatergic signalling and astrocytic functioning. Omics data analysis can facilitate the assessment of these mechanisms and help to identify new therapeutic strategies. The aim of this study was to curate and publish interactive biological pathways involved in schizophrenia for the identification of novel pharmacological targets implementing pathway, gene ontology, and network enrichment analysis. Methods Neuroinflammatory pathways were created using PathVisio and published in WikiPathways. A transcriptomics dataset, originally created by Narla et al. was selected for data visualisation and analysis. Gene ontology terms and pathways were obtained for differentially expressed genes using g:Profiler and BiNGO. Transcriptomics data was visualised within the curated pathways. Cytoscape was used for network-based gene set and pathway enrichment analyses. Networks were extended with transcription factors, pathways, and drugs and then network hubs were determined based on degrees of connectivity. Results Glutamatergic, immune, and astrocytic signalling as well as extracellular matrix reorganisation were altered in schizophrenia while we did not find an effect on the complement system. The alterations might impair neural development and maintenance. Transcription factor networks revealed complex interactions between transcription factors, transporters, and inflammatory receptors. We also report pharmacological agents that target the glutamate receptor subunits, inflammatory mediators, and metabolic enzymes found. Conclusion New neuroinflammatory pathways incorporating the extracellular matrix, glutamatergic neurons, and astrocytes in the aetiology of schizophrenia were established. Transcriptomics based network analysis provided novel targets, including extra-synaptic glutamate receptors, glutamate transporters and extracellular matrix molecules that can be evaluated for therapeutic strategies.