Role of Complement C4 in Brain Ventricle Enlargement

Abstract

Complement C4A has been identified as a risk allele for schizophrenia (SCZ), with higher C4A copy number correlating to an increased susceptibility to this disorder. Notably, SCZ patients often exhibit ventriculomegaly, a condition characterized by the enlargement of brain ventricles and the accumulation of cerebrospinal fluid (CSF). However, the mechanisms underlying ventriculomegaly remain elusive. In a previous study, our laboratory has established a transgenic mouse model that over-expresses human C4A. These mice exhibited increased anxiety, abnormal social behavior, and memory defects that were associated with microglia-dependent synapse loss, symptoms also prevalent in schizophrenia patients. Interestingly, through serial slicing of cerebral cortical tissues from -2.888 mm to -1.955 mm posterior to bregma at 300-micrometer intervals, we observed a higher incidence of ventriculomegaly in human C4A overexpressing mice compared to controls. This phenotype was consistent across multiple mouse cohorts. To investigate the role of complement C4A in the ventriculomegaly, we focused on the choroid plexus (ChP), a key site for CSF secretion and a critical barrier tissue. We hypothesize that alterations in the ChP could cause ventriculomegaly through two possible mechanisms: (1) excessive CSF secretion and (2) alterations in CSF composition leading to flow obstruction, resulting in CSF accumulation, and increased ventricular pressure, ultimately causing ventriculomegaly. We aim to understand the molecular changes caused by C4A overexpression that may contribute to ventriculomegaly by performing bulk RNA sequencing of the ChP. Our results indicated differential gene expressions in water channel, cilia motor protein, and interferon-related genes in the choroid plexus (ChP) of C4A overexpressing mice. These genes and interferon signaling pathways were not observed in cerebral cortex bulk RNA sequencing, suggesting a ChP-specific inflammatory response. In addition, immunofluorescence staining revealed increased immune cell presence in the ChP, especially the CD45+ CD11b+ myeloid populations, in mice with higher copies of HC4A, further supporting local inflammation. Overall, this study elucidated that C4A overexpression could contribute to local inflammation in the ChP, potentially disrupting homeostasis and water secretion, which might provide a mechanistic link to the ventriculomegaly commonly observed in schizophrenia patients. While the direct impact of ventriculomegaly on schizophrenia's cognitive, behavioral, or psychological symptoms remains unclear, its association with the disorder suggests it can serve as a potential biomarker or prescreening tool for neuropsychiatric conditions. Moreover, C4A's role in ventriculomegaly and synaptic pruning underscores the value of investigating therapeutic targets beyond traditional antipsychotics, potentially offering new treatment avenues for schizophrenia.