Abstract
Zinc is important in neural and synaptic development and neuronal transmission. Within the brain, zinc transporter 3 (ZnT3) is essential for zinc uptake into vesicles. Loss of vesicular zinc has been shown to produce neurodevelopmental disorder (NDD)-like behavior, such as decreased social interaction and increased anxiety- and repetitive-like behavior. Maternal immune activation (MIA) has been identified as an environmental factor for NDDs, such as autism spectrum disorders (ASDs) and schizophrenia (SZ), in offspring, which occurs during pregnancy when the mother’s immune system reacts to the exposure to viruses or infectious diseases. In this study, we investigated the interaction effect of a genetic factor [ZnT3 knockout (KO) mice] and an environmental factor (MIA). We induced MIA in pregnant female (dams) mice during mid-gestation, using polyinosinic:polycytidylic acid (polyI:C), which mimics a viral infection. Male and female ZnT3 KO and wild-type (WT) offspring were tested in five behavioral paradigms: Ultrasonic Vocalizations (USVs) at postnatal day 9 (P9), Open Field Test, Marble Burying Test, three-Chamber Social Test, and Pre-pulse Inhibition (PPI) in adulthood (P60–75). Our results indicate that loss of vesicular zinc does not result in enhanced ASD- and SZ-like phenotype compared to WT, nor does it show a more pronounced phenotype in male ZnT3 KO compared to female ZnT3 KO. Finally, MIA offspring demonstrated an ASD- and SZ-like phenotype only in specific behavioral tests: increased calls emitted in USVs and fewer marbles buried. Our results suggest that there is no interaction between the loss of vesicular zinc and MIA induction in the susceptibility to developing an ASD- and SZ-like phenotype.
Highlights
Brain development is a complex process that is influenced by genetic and environmental factors
We previously hypothesized that dams injected with polycytidylic acid (polyI):C would demonstrate a loss of weight 24-h post-injection, and saline-injected dams would continue gaining weight consistently
As for sensorimotor gating measured in the Pre-pulse Inhibition (PPI) test, a deficit was observed in female zinc transporter 3 (ZnT3) KO offspring of polyI:Cinjected mothers and greater inhibition was observed in female offspring of polyI:C-injected mothers
Summary
Brain development is a complex process that is influenced by genetic and environmental factors. The development of the central nervous system, which begins in the early embryonic stages, includes various critical periods of vulnerability, at which point alterations to the fetal environment can result in structural and functional abnormalities in offspring organs, including the brain (Rice and Barone, 2000; Schlotz and Phillips, 2009) This could lead to increased susceptibility to diseases and psychiatric disorders later in life as physiological changes may occur in the process (Rice and Barone, 2000; Schlotz and Phillips, 2009). During pregnancy, maternal immune activation (MIA) can lead to changes in the fetal environment, contributing to the disruption of brain development in exposed offspring (Meyer, 2014) Zinc deficiency is another risk factor that has been identified as a contributor to neurodevelopmental disorders (NDDs), such as autism spectrum disorders (ASDs) and schizophrenia (SZ) (Yasuda et al, 2011; Grabrucker, 2013; Nuttall, 2017; Ha et al, 2018; Joe et al, 2018). Zinc transporter 3 (ZnT3) is important for the uptake of zinc into vesicles and it is expressed in zinc-enriched areas such as the cerebral cortex, amygdala, and hippocampus [as depicted by Cole et al (1999) using modifications of Timm’s silversulfide stain]
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