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

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. 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. 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. 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.

精神分裂症（Schizophrenia）是一种累及全球1%人群的精神障碍。现有研究证据表明，神经炎症（neuroinflammation）可通过改变神经发育过程，并特异性影响谷氨酸能信号传导（glutamatergic signalling）与星形胶质细胞功能（astrocytic functioning），参与该疾病的病理进程。本研究旨在整理与精神分裂症相关的交互式生物通路，通过通路分析、基因本体（gene ontology）分析与网络分析，以识别新型药理学靶点。本研究使用PathVisio软件构建神经炎症通路，并将其发布于WikiPathways平台。本研究选用了Narla等人最初构建的转录组学（transcriptomics）数据集用于数据可视化与分析。将转录组学数据映射至通路与网络中，并补充了转录因子（transcription factors）、相关通路及药物信息。基于连接度确定网络枢纽节点。精神分裂症患者的谷氨酸能、免疫及星形胶质细胞信号传导，以及细胞外基质（extracellular matrix）重构均发生异常，但未观察到补体系统（complement system）出现相关改变。本研究识别出了靶向谷氨酸受体亚基、炎症介质及代谢酶的药理学制剂。本研究构建了整合细胞外基质、谷氨酸能神经元与星形胶质细胞的精神分裂症病因学（aetiology）新型神经炎症通路。基于转录组学的网络分析为治疗策略研发提供了新型靶点，包括突触外谷氨酸受体（extra-synaptic glutamate receptors）、谷氨酸转运体（glutamate transporters）及细胞外基质分子，这些靶点均可进一步开展治疗性评估。