Laboratory of Molecular Biology, Department of Biofunctional Analysis, Gifu Pharmaceutical University, Gifu, Japan.
J Neurosci Res. 2011 Oct;89(10):1575-85. doi: 10.1002/jnr.22704. Epub 2011 Jul 5.
Maternal infection during pregnancy is an environmental risk factor for the development of severe brain disorders in offspring, including schizophrenia and autism. However, little is known about the neurodevelopmental mechanisms underlying the association between prenatal exposure to infection and the emergence of cognitive and behavioral dysfunctions in later life. By injecting viral mimetic polyriboinosinic-polyribocytidylic acid (Poly I:C) into mice, we investigated the influence of maternal immune challenge during pregnancy on the development of the cerebral cortex of offspring. Our previous study showed that stimulation of the maternal immune system compromised the expression properties of transcription factors and the synaptogenesis of cortical neurons in upper layers but not those in deeper layers. The objective of the current study was to examine further whether maternal immune challenge has an influence on the cellular-biological features of the cortical progenitors that generate distinct cortical neuronal subtypes. We found the following abnormalities in the cortex of mice given the prenatal Poly I:C injection during later stages of cortical neurogenesis. First, proliferative activity and the expression of Pax6, which is a master regulator of the gene expression of transcription factors, were significantly decreased in the cortical progenitors. Second, the laminar allocation and gene expression were significantly altered in the daughter neurons generated at the same birth dates. These results demonstrate that specific abnormalities in the cortical progenitors preceded deficits in neuronal phenotypes. These changes may underlie the emergence of psychiatric brain and behavioral dysfunctions after in utero exposure to an infection.
母体怀孕期间感染是导致后代出现严重脑部疾病（包括精神分裂症和自闭症）的环境风险因素。然而，对于产前感染与生命后期认知和行为功能障碍之间的关联的神经发育机制，我们知之甚少。通过向小鼠注射病毒模拟物聚肌胞苷酸（Poly I:C），我们研究了母体怀孕期间免疫挑战对后代大脑皮层发育的影响。我们之前的研究表明，刺激母体免疫系统会损害转录因子的表达特性和皮质神经元在上层的突触发生，但不会损害深层的。本研究的目的是进一步研究母体免疫挑战是否会影响产生不同皮质神经元亚型的皮质祖细胞的细胞生物学特征。我们发现，在皮质神经发生后期给予产前 Poly I:C 注射的小鼠皮质中存在以下异常。首先，皮质祖细胞的增殖活性和 Pax6 的表达显著降低，Pax6 是转录因子基因表达的主要调节因子。其次，在同一天出生的子神经元中的层分配和基因表达发生了显著改变。这些结果表明，皮质祖细胞的特定异常先于神经元表型缺陷。这些变化可能是宫内感染后出现精神疾病脑和行为功能障碍的基础。
