Environmental Toxins and Microglia-Synapse Interactions in Autism

项目摘要 自闭症中的环境毒素和小胶质细胞-突触相互作用。 越来越明显的是，不同的基因和环境暴露(S)结合或协同作用产生了 自闭症表型的谱系取决于关键的发育窗口。多胎/多母 环境毒素和暴露已经与人类自闭症联系在一起，但单一因素的关联 一直相对较弱。这表明，是多个母亲暴露在一起增加了 后代的脆弱性。我们现在认识到，非化学应激源，如有限的资源或社会压力 母亲的支持会增加胎儿对化学应激源暴露的脆弱性(例如，污染或 毒素)，这可以解释为什么单独接触或隔离的风险因素是自闭症的适度预测因素 风险。旨在破译导致ASD的机制的模型存在过度简化的问题，使用 单一特工。我们通过使用一种新的模型来打破这一差距，该模型使用了行为学上的综合效应 相关的母体应激源和与环境相关的污染物、柴油废气，这两者都已 与自闭症有关。我们发现母亲接触柴油废气颗粒物(DEP)与母亲 压力(MS)(但都不是孤立的)会导致早期沟通障碍和长期认知障碍 并且显著增加了雄性后代的焦虑，而不是雌性后代。我们证明了接触环保局的证据 显著改变小胶质细胞在男性胚胎脑中的定植，而不是女性胚胎脑，并结合产前 DEP和MS暴露导致大鼠同脑区小胶质细胞功能的持续性变化 男性。除了在大脑的先天免疫防御中的功能外，小胶质细胞也是 发育过程中依赖经验的突触重塑。有人建议小胶质细胞修剪 不适当或较弱的突触，同时保留适当或较强的连接。自闭症一直很好 被描述为突触功能障碍的疾病，功能网络分析几乎都指出 控制活性依赖型突触重构的分子通路在脑血管病发病机制中的重要性 自闭症。重要的是，小胶质细胞介导的修剪受损破坏了小鼠的大脑功能连接和 社交行为，强烈表明小胶质细胞-突触的相互作用可能有助于自闭症的发生 病理生理学。因此，这里要检验的具体假设是，小胶质细胞通过联合 环境因素会导致这些细胞异常的突触修剪，导致神经回路 功能障碍和ASD样行为。

Project Summary Environmental toxins and microglia-synapse interactions in autism. It is increasingly evident that diverse genes and environmental exposure(s) combine or synergize to produce a spectrum of autism phenotypes dependent upon critical developmental windows. Multiple prenatal/maternal environmental toxins and exposures have been linked to human ASDs, but the associations of single agents have been relatively weak. This suggests it is the combination of multiple maternal exposures that increases vulnerability in offspring. We now recognize that non-chemical stressors, such as limited resources or social support of the mother, can increase vulnerability of the fetus to chemical stressor exposures (e.g., pollution or toxins), which could explain why a single exposure or risk factor in isolation is a modest predictor of autism risk. Models aimed at deciphering the mechanisms that contribute to ASD suffer from oversimplification, using single agents. We breach this gap by using a new model that employs the combined effects of an ethologically relevant maternal stressor and environmentally relevant pollutant, diesel exhaust, both of which have been implicated in autism. We show that maternal diesel exhaust particle (DEP) exposure combined with maternal stress (MS) (but neither in isolation) produces early-life communication deficits, and long-term cognitive deficits and strikingly increased anxiety in male but not female offspring. We show evidence that DEP exposure significantly alters microglial colonization of the male but not female embryonic brain, and combined prenatal DEP and MS exposure leads to persistent changes in the function of microglia of the same brain regions of males. Beyond their functions in innate immune defense of the brain, microglia are important regulators of experience-dependent synaptic remodeling during development. It is proposed that microglia prune inappropriate or weak synapses while sparing appropriate or strong connections. Autism has been well described as a disease of synaptic dysfunction, and functional network analyses have nearly all pointed out the importance of molecular pathways that control activity-dependent synaptic remodeling in the pathology of ASDs. Importantly, impaired microglia-mediated pruning in mice disrupts functional brain connectivity and social behavior, strongly suggesting that microglia-synapse interactions may contribute to autism’s pathophysiology. Thus, the specific hypothesis to be tested here is that microglial activation by combined environmental factors will cause aberrant synaptic pruning by these cells, leading to neural circuit dysfunction and ASD-like behaviors.