Blood-Brain Barrier Leakiness and Inflammation in Schizophrenia: Implications for Dopamine Alterations

About This Grant

Project Summary Schizophrenia is a severe chronic mental illness characterized by both dopamine dysregulation and neuroinflammation known to alter neural function. Neuroinflammation leads to a leaky blood-brain barrier (BBB), and damages dopamine neurons. By studying midbrain tissue using single-cell RNA sequencing, we can identify the damaging molecular communication pathways that resident immune cells and invading immune cells use to disrupt brain homeostasis. We will determine how endothelial cells are transcriptionally and morphologically changed during brain inflammation, which will open new avenues to support strengthening the BBB as a treatment in schizophrenia. We will focus on the inflammatory environment in the schizophrenia midbrain, where we have discovered elevated cytokine and complement expression along with gliosis and macrophage infiltration. Our study will examine multiple related inflammatory pathways that mediate neuronal damage and assess whether the transcriptional profile, number, or size of dopamine neurons differs with inflammation and schizophrenia diagnosis. We will determine and map the key molecular and cellular changes underpinning a "leaky" BBB in proximity to dopamine neurons in the midbrain of people with schizophrenia. Additionally, we will identify serum biomarkers that distinguish high and low inflammatory states and correlate with leaky BBB status in the midbrain by linking central (brain) and peripheral measures (blood) using machine learning. This will allow the field to prioritize blood biomarkers that can be used to identify those most likely to benefit from anti-inflammatory and BBB treatments and to track potential benefits of treatment over time. Ultimately, this research will deepen our understanding of schizophrenia neuropathology and contribute to the development of novel therapies aimed at inflammatory changes to the BBB.