Neuroinflammatory Signatures of Complement Component 4 in the Subventricular Zone of Autism Spectrum Disorder and Schizophrenia
AuthorMou, Ta-Chung M.
Lane, Malcolm V.
Ireland, Derek D.C.
Tonelli, Leonardo H.
Clark, Sarah M., Ph.D.
MetadataShow full item record
AbstractIn addition to an early inflammatory insult, genetic variants that impinge upon immune function are among the most recognized risk factors associated with neurodevelopmental psychiatric disorders. Among these, complement component 4 (C4), a molecule involved in inflammatory responses, has been strongly associated with schizophrenia (SZ). However, whether C4 is involved in other neurodevelopmental disorders, such as autism (ASD), is a matter of ongoing investigation. Moreover, while C4 in SZ has been implicated in the context of synaptic pruning, little is known about its neuroinflammatory role. The subventricular zone (SVZ) is a region heavily involved in neurodevelopment and neuroimmune interactions through the lifespan; thus, it is a region wherein C4 may play a vital role in disease pathology. 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+ progenitor cells. Examination of mRNA levels showed elevated C4 in both ASD and SZ, with higher expression in SZ compared to 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 immune dysregulation without a strong association with known infectious pathways. 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. Moreover, the number of Ki67+ cells was significantly higher in ASD compared to SZ and controls. Taken together, these results support a role for C4 into inflammatory-neuroimmune dysregulation observed in SZ and ASD pathology.
DescriptionPoster presented at Immunology 2022, May 6-10, 2022
Rights/TermsAttribution-NonCommercial-NoDerivatives 4.0 International
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/18691
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Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International