Abstract
Zika virus (ZIKV) has emerged as a significant public health concern due to its association with severe neurological outcomes in infants, including microcephaly and congenital Zika syndrome (CZS). However, while the majority of ZIKV infections during pregnancy do not result in CZS, the potential long-term neurological effects of mild or inapparent maternal infections remain poorly understood. In this study, we adapted a model of maternal ZIKV infection in human STAT2 knock-in (hSTAT2) mice to investigate the effects of ZIKV infection during mid-gestation, aiming to mirror typical asymptomatic infections as they occur in humans. We found that maternal ZIKV infection at mid-gestation leads to vertical transmission without causing overt developmental deficits or clinical signs in dams or offspring. Despite the absence of immediate clinical signs, transcriptomic analyses revealed significant changes in the developing fetal brain, particularly in genes related to synaptic function and neuronal development. These molecular alterations were associated with increased synaptic density in the hippocampus and heightened susceptibility to chemically induced seizures in offspring, suggesting subtle yet significant long-term neurological consequences. Using motion sequencing (MoSeq), an unsupervised machine learning approach that profiles naturalistic motor behavior, we also identified persistent, sex-biased alterations in the content and structure of spontaneous behavior in offspring exposed to maternal ZIKV infection. Our findings highlight that even mild maternal ZIKV infections can disrupt fetal neurodevelopment, underscoring the need for enhanced monitoring and public health measures for children exposed to ZIKV in utero but who do not experience severe developmental alterations at birth. Additionally, our study provides a valuable animal model and comprehensive, cell type-specific transcriptomic datasets that will facilitate new lines of investigation into the impact of inapparent maternal ZIKV infections on fetal and childhood brain development.