Congenital toxoplasmosis induces NMDA receptor hypofunction and neuroinflammation associated with neurobehavioral abnormalities in adult mice.

Maternal infection with Toxoplasma gondii can disrupt fetal brain development, yet the mechanisms underlying the long-term neurobehavioral consequences of congenital toxoplasmosis remain incompletely understood. In this study, we investigated the effects of congenital toxoplasmosis on adult offspring behavior, with particular emphasis on how the gestational timing of maternal infection and offspring sex influence the nature and severity of these alterations. We also evaluated neuroinflammation, neurotrophism, and N-methyl-d-aspartate receptor (NMDAR) subunit expression. Pregnant dams were infected with T. gondii tachyzoites on gestational days (GD) 5, 12, or 17, and offspring of both sexes were assessed in early adulthood (8 weeks) using the open-field, elevated plus maze, Y-maze, and marble burying tests. Brain mRNA expression levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF), and the NMDAR subunits NR1 and NR2A were also quantified. Congenital infection induced hyperactivity, increased anxiety-like behavior, impaired spatial working memory, and enhanced repetitive behaviors. Molecular analyses revealed significantly elevated IL-6 and TNF-α mRNA levels, accompanied by reduced expression of BDNF, NR1, and NR2A. These effects were most pronounced following early- (GD-5) and mid-gestational (GD-12) infection, which were also associated with greater brain cyst burden and more severe neuroinflammation. Male offspring exhibited more pronounced neuroinflammatory and behavioral alterations than females infected at the same gestational stage. Taken together, these findings demonstrate that congenital toxoplasmosis produces behavioral and molecular abnormalities in adult mice and suggest that gestational timing and sex are important determinants of severity and long-term neurodevelopmental outcomes.