Maternal immune activation, cytokines, and the pathogenesis of autism

描述（由申请人提供）：自闭症谱系障碍（ASD）是一种复杂的疾病，似乎是由遗传变化和早期发育过程中的环境损伤引起的。越来越多的证据表明，几个这样的环境侮辱工作的机制，收敛到长期激活细胞因子在胎儿和出生后早期的大脑发育。母体感染的小鼠模型的发展为母体免疫激活（MIA）和ASD的一些病理特征之间的联系提供了强有力的支持。最引人注目的MIA小鼠模型-PolyI：C注射-产生与自闭症个体相似的基因表达、神经解剖学、神经化学和行为变化的异常。目前的证据表明，MIA对胎儿脑发育的这些影响是由穿过胎盘的细胞因子介导的。 虽然对母体细胞因子如何改变胎儿大脑发育知之甚少，但我们将在本提案中测试的最有可能的可能性是MIA导致慢性神经炎症，改变大脑发育和行为，并可能导致ASD的症状和病理。虽然细胞因子通常被认为是介导免疫反应，但这些小蛋白及其受体存在于健康的发育中的CNS中，它们在神经发育和可塑性中发挥重要作用。由于细胞因子介导免疫反应，存在于发育中的皮质中，并改变皮质可塑性和连接性，因此改变发育中大脑中细胞因子的因素可能导致突触连接性的变化，从而导致ASD。本建议的目标是定义在MIA后不同出生后年龄的后代CNS特定区域中发生变化的细胞因子的完整补充，并确定这些细胞因子对皮质神经元连接和功能的影响。使用MIA的PolyI：C小鼠模型、Luminex多重细胞因子阵列、免疫细胞化学和组织化学、细胞和切片培养以及全细胞膜片钳记录，我们将解决以下目标。(1)定义MIA后后代四个不同脑区细胞因子变化的性质和时间过程。(2)在出生后早期发育过程中测试改变的细胞因子对突触连接和功能的组合。该提案的结果将深入了解MIA对大脑发育和功能影响的机制，并可能确定ASD治疗干预的新靶点。 公共卫生相关性：虽然广泛的环境刺激已被提出在自闭症谱系障碍的发病机制中发挥作用，但这些刺激中的许多都具有改变免疫功能的能力。由于细胞因子介导免疫反应，存在于发育中的大脑中，并调节皮质可塑性和连接性，因此在发育期间改变细胞因子的因素可能导致突触连接性的变化，从而导致ASD。本建议的目标是定义的细胞因子的完整的补充，改变在特定区域的中枢神经系统的后代在不同的出生后年龄以下MIA，并确定这些细胞因子的连接和功能的影响，在相关的出生后年龄在几个皮质区域。

DESCRIPTION (provided by applicant): Autism spectrum disorder (ASD) is a complex disease that appears to be caused by a combination of genetic changes and an environmental insult during very early development. Increasing evidence suggests that several such environmental insults work through mechanisms that converge to chronically activate cytokines during fetal and early postnatal brain development. The development of a mouse model for maternal infection has added strong support for a link between maternal immune activation (MIA) and some of the pathology characteristic of ASD. The most compelling MIA mouse model-PolyI:C injection-produces abnormalities in gene expression, neuroanatomy, neurochemistry, and behavioral changes that are similar to those in autistic individuals. Current evidence indicates that these effects of MIA on fetal brain development are mediated by cytokines that cross the placenta. Although little is known about how maternal cytokines alter fetal brain development, the most likely possibility that we will test in this proposal is that MIA leads to chronic neuroinflammation that alters brain development and behavior and may contribute to the symptoms and pathology of ASD. Although cytokines are most often thought of as mediating an immune response, these small proteins and their receptors are found in the healthy, developing CNS where they play important roles in neural development and plasticity. Since cytokines mediate the immune response, are present in the developing cortex, and alter cortical plasticity and connectivity, factors that alter cytokines in the developing brain may lead to changes in synaptic connectivity that contribute to ASD. The goals of this proposal are to define the full complement of cytokines that are changed in specific regions of the CNS of offspring at various postnatal ages following MIA and to determine the effects of those cytokines on cortical neuron connectivity and function. Using the PolyI:C mouse model of MIA, Luminex multiplex cytokine arrays, immunocyto- and histochemistry, cell and slice culture, and whole-cell patch-clamp recording, we will address the following Aims. (1) Define the nature and time-course of changes in cytokines n four distinct brain regions of offspring following MIA. (2) Test combinations of altered cytokines on synaptic connectivity and function during early postnatal development. Results from this proposal will provide insight into the mechanism underlying the effects of MIA on brain development and function and will potentially identify novel targets for therapeutic intervention in ASD. PUBLIC HEALTH RELEVANCE: Although a wide range of environmental stimuli have been proposed to play a role in the pathogenesis of autism spectrum disorders, many of these stimuli have in common the ability to alter immune function. Since cytokines mediate the immune response, are present in the developing brain, and regulate cortical plasticity and connectivity, factors that alter cytokines during development may lead to changes in synaptic connectivity that contribute to ASD. The goals of this proposal are to define the full complement of cytokines that are changed in specific regions of the CNS of offspring at various postnatal ages following MIA and to determine the effects of those cytokines on connectivity and function in several cortical regions at the relevant postnatal ages.