Discovering links between inflammation, neurogenesis, brain structure and brain function in schizophrenia

Genetic, epidemiological and post-mortem studies implicate inflammation in the pathogenesis of schizophrenia. While inflammation can regulate neurogenesis, and is associated with brain structural and functional abnormalities, research addressing the link between inflammation and neurobiology in schizophrenia is limited. In the subependymal zone (SEZ), the brain’s largest niche for neurogenesis, I discovered vast differences across the whole transcriptome in schizophrenia compared to controls (post-mortem cohort n=20-21/group). CD163, a macrophage marker, had significantly increased expression in schizophrenia. Overall, genes in immune pathways were significantly upregulated, whereas genes in neurogenesis promoting pathways were significantly downregulated in schizophrenia along with reduced markers for all stages of neurogenesis. In a larger cohort, including bipolar disorder (n=29-32/group), macrophage cell density was increased specifically in schizophrenia. Cluster analysis of inflammation genes defined heightened inflammation subgroups comprising 37% of schizophrenia cases, 32% of bipolar disorder cases and only 10% of controls. The high inflammation schizophrenia subgroup had increased peripheral immune cell marker mRNAs, increased macrophage density, and altered markers for neurogenesis in the neurogenic niche suggesting increased stem cell quiescence and reduced neuronal progenitor cells and newborn neurons. These findings were replicated in an independent cohort (n=20-22). An analysis comparing the transcriptomes of high and low inflammation schizophrenia subgroups revealed that heightened inflammation alters the SEZ microenvironment by increasing angiogenesis and extracellular matrix stiffness, suggesting a fibrotic state. These changes likely increase blood-brain-barrier permeability and immune cell infiltration, and alter neuronal differentiation and migration. Allowing for translation potential of this research, I identified that peripheral inflammation marker, C-reactive protein (CRP), was increased in schizophrenia in a living cohort (n=1143). Increased CRP was associated with poorer attention ability and reduced cortical thickness in the caudal middle frontal, pars opercularis and posterior cingulate cortices in schizophrenia (MRI subset n=293). This thesis elucidated the molecular and cellular contribution of inflammation to aberrant neurogenesis in schizophrenia. Future manipulation of the identified cells and processes may enable the restoration of neurogenesis in schizophrenia and allow us to harness its potential for regenerative treatments. Further, inflammation biomarkers that have cognitive and brain structural relevance could identify schizophrenia patients who may benefit most from adjunctive treatment of inflammation