Neuroinflammation as a therapeutic target for schizophrenia: RNA sequencing of downstream molecular pathways

Overview

This research program investigates neuroinflammation as a novel therapeutic target for schizophrenia, focusing on the downstream molecular pathways through which inflammation disrupts brain function. Approximately 50% of individuals with schizophrenia show elevated neuroinflammation, which is thought to trigger a cascade of neural events contributing to symptoms. Because broadly acting anti-inflammatory drugs (such as aspirin) have shown limited benefit when combined with antipsychotics, this project aims to identify more precise molecular targets downstream of the inflammatory response. By mapping these pathways, the research seeks to enable targeted therapies that address the harmful effects of neuroinflammation without disrupting the signalling cascades necessary for healthy brain function.

The project has direct implications for pharmaceutical development, offering a pathway to identify candidate compounds that modulate dopaminergic and glutamatergic neurotransmission in inflammatory subtypes of schizophrenia.

Technical specifications

Research approach:

• Uses an established mouse model of acute neuroinflammation (twice-daily lipopolysaccharide treatment) that recapitulates schizophrenia-like behaviours, including amphetamine-induced hyperlocomotion and prefrontal glutamatergic dysregulation
• Applies RNA sequencing (RNASeq) to analyse transcriptome changes in schizophrenia-relevant brain regions: prefrontal cortex and midbrain
• Includes both male and female mice (12 per group) to capture sex-specific pathway responses
• Employs Ingenuity Pathway Analysis to predict downstream targets and signalling cascades activated by neuroinflammation
• Performs predictive compound modelling to identify drug candidates that target identified pathways and alter dopamine or glutamate cell function
• Builds on prior human postmortem data showing reduced dopamine transporter and glutamate receptor mRNA in high-inflammation schizophrenia patients

Key pathways under investigation:

• Complement cascade activation
• Apoptosis pathways
• Kynurenine pathway and its effect on glutamatergic receptor function
• Dopaminergic cell dysregulation

Technology readiness level

The project is at an early-to-mid research stage, with the mouse model already validated and published (Oliveros et al., 2017). Collaborators have previously demonstrated high and low inflammation subgroups in postmortem schizophrenia tissue (Fillman et al., 2013). The current one-year study will generate new transcriptomic data and predictive compound analyses to identify candidate therapeutic targets. Parallel work funded by NSW Health will validate findings in human postmortem tissue. The research is positioned to generate actionable drug target hypotheses suitable for subsequent in vivo testing and pharmaceutical development partnerships.