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

Abstract

Objectives

Schizophrenia is a psychiatric disorder affecting 1% of the population. 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. The aim of this study was to curate interactive biological pathways involved in schizophrenia for the identification of novel pharmacological targets implementing pathway, gene ontology, and network 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. Transcriptomics data was visualised within pathways and networks, extended with transcription factors, pathways, and drugs. 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. Pharmacological agents that target the glutamate receptor subunits, inflammatory mediators, and metabolic enzymes were identified.

Conclusions

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.

Keywords:

• Neuroinflammation
• schizophrenia
• metabolic signalling
• pathway models
• network analysis
• molecular pathways

Acknowledgements

None.

Statement of interest

None to declare.

Additional information

Funding

PM received funding from ZonMW/NOW – Aspasia Program Researcher (argenx, Grant number 1,50,11,033), Apellis Pharmaceuticals - (Researcher initiated (https://apellis.com/)), Westerdijk foundation - Researcher initiated (https://stichtingjohannawesterdijkfonds.sites.uu.nl/), Brain Foundation of the Netherlands - (Researcher initiated (https://www.hersenstichting.nl/) grant number PI20/00153), EU - Interreg Euregion (EU-EURLIPID), NIH - Pathogenic mechanisms of MusK Myasthenia gravis (4224868), NIH - Rare Disease Network for Myasthenia Gravis (18-003826), and EU - Horizon 2020 (EJP RD Grant number N°825575).