Sandoval Katy Celina, Thackray Sarah E, Wong Alison, Niewinski Nicole, Chipak Colten, Rehal Suhkjinder, Dyck Richard H
Department of Psychology, University of Calgary, Calgary, AB, Canada.
Hotchkiss Brain Institute (HBI), University of Calgary, Calgary, AB, Canada.
Front Behav Neurosci. 2022 Feb 22;16:769322. doi: 10.3389/fnbeh.2022.769322. eCollection 2022.
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.
锌在神经和突触发育以及神经元传递中起着重要作用。在大脑中，锌转运体3（ZnT3）对于锌摄取到囊泡中至关重要。囊泡锌的缺失已被证明会产生类似神经发育障碍（NDD）的行为，如社交互动减少以及焦虑和重复样行为增加。母体免疫激活（MIA）已被确定为后代患NDD（如自闭症谱系障碍（ASD）和精神分裂症（SZ））的一个环境因素，这发生在孕期，当母亲的免疫系统对病毒或传染病暴露产生反应时。在本研究中，我们调查了一个遗传因素（ZnT3基因敲除（KO）小鼠）和一个环境因素（MIA）的相互作用效应。我们在妊娠中期使用聚肌苷酸：聚胞苷酸（polyI:C）诱导怀孕雌性（母鼠）小鼠发生MIA，polyI:C可模拟病毒感染。对雄性和雌性ZnT3 KO及野生型（WT）后代进行了五项行为范式测试：出生后第9天（P9）的超声波发声（USV）、旷场试验、埋珠试验、三室社交试验以及成年期（P60 - 75）的前脉冲抑制（PPI）。我们的结果表明，与WT相比，囊泡锌的缺失并不会导致更严重的ASD和SZ样表型，并且与雌性ZnT3 KO相比，雄性ZnT3 KO也未表现出更明显的表型。最后，MIA后代仅在特定行为测试中表现出ASD和SZ样表型：USV中发出的叫声增加以及埋珠数量减少。我们的结果表明，在易患ASD和SZ样表型方面，囊泡锌缺失与MIA诱导之间不存在相互作用。
