Neuroinflammatory Signatures of Complement Component 4 in the Subventricular Zone of Autism Spectrum Disorder and Schizophrenia

Abstract

Abstract Early inflammatory insults are the most recognized environmental risk factor associated with neurodevelopmental psychiatric disorders. The subventricular zone (SVZ) is a region heavily involved in neurodevelopment and neuroimmune interactions through the lifespan. Complement component 4 (C4), a classical molecule involved in inflammatory responses, has been associated with schizophrenia (SZ) by genetic studies. However, whether C4 is involved in other neurodevelopmental disorders, such as autism (ASD), is a matter of current studies. Moreover, while C4 in SZ has been studied in the context of synaptic pruning, little is known about its neuroinflammatory role. Using in situ hybridization with radioactive riboprobes and RNAscope, we identified robust astrocytic expression of C4 in the SVZ and in the septum pellucidum. C4 was also expressed in ependyma, neurons, and Ki67+ cells, but not microglia, with higher expression in SZ as compared to controls and ASD. Moreover, the number of Ki67+ cells was significantly higher in ASD compared to SZ and controls. Targeted transcriptomic analysis of inflammatory pathways revealed a strong association of complement system genes with SZ, and to a lesser extent ASD, as well as generalized inflammation without an association with known infectious pathways. Additional analysis of differentially expressed genes (DEGs) showed that ASD DEGs were enriched in adaptive immune system functions such as Th cell differentiation, while SZ DEGs were enriched in innate immune system functions, including NF-κB and toll like receptor signaling. Taken together, these results support a role for C4 into inflammatory-neuroimmune dysregulation observed in SZ and ASD pathology. Supported by National Institutes of Mental Health grant P50 MH103222 (Silvio O. Conte Center for Translational Mental Health Research).