In Utero Exposure to Zika Virus Results in sex-Specific Memory Deficits and Neurological Alterations in Adult Mice

Transplacental transmission of Zika virus (ZIKV) during early pregnancy may lead to several neurological alterations, known as congenital Zika syndrome. We have previously shown that intravaginal infection of immunocompetent dams with ZIKV during the early stage of pregnancy triggers neuroinflammation in fetuses, characterized by increased brain expression of inflammatory factors, including IL-6, IL-18, CCL2, CXCL1, and CXCL10. The present study sought to understand the long-term consequences of these early cerebral alterations. For that, pregnant FVB/NJ immunocompetent females were infected intravaginally on the gestational day (GD) 4.5 and experiments were performed when offspring reached between 4 to 5 months of age. The exposure to ZIKV promoted significant neuronal cell loss detected in the CA1 region of the hippocampus of adult mice. However, only females showed reduced expression levels of brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD95), and syntaxin-1A, which are important genes related to neuronal function and synaptic plasticity. Moreover, the protein levels of the pre- and postsynaptic markers, SNAP25 and PSD95, respectively, were decreased exclusively in ZIKV-exposed female mice, indicating that ZIKV exposure in utero induces synaptic loss. Additionally, only females exposed to ZIKV showed risk-taking behavior and hippocampal-dependent spatial memory deficit. Together, these results demonstrate that intravaginal infection of mice on GD4.5 induces neurological alterations in the offspring detectable in their adulthood and that female mice, rather than male mice, are more susceptible to ZIKV-induced neurobehavioral alterations. SUMMARY STATEMENT: In utero exposure to ZIKV leads to decreased number of neurons in adult mice. Female mice exposed to ZIKV in utero exhibit lower levels of BDNF, a decrease in synaptic markers, memory deficits, and risk-taking behavior during adulthood.