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联合收割机或协同作用产生了一种 自闭症表型谱取决于关键的发育窗口。多次产前/孕产妇 环境毒素和暴露与人类ASD有关，但单一因子的关联 相对薄弱。这表明，母亲多次暴露的组合增加了 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 母亲的支持，可以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一暴露或孤立的风险因素是自闭症的适度预测因子 风险旨在破译导致ASD的机制的模型过于简单化，使用 单一代理我们通过使用一种新的模型来突破这一差距，该模型采用了行为学上的 相关的母亲压力源和环境相关的污染物，柴油机废气，这两者都已被 与自闭症有关我们发现，母亲的柴油机排气颗粒（DEP）暴露结合母亲的 压力（MS）（但不是孤立的）会导致早期的沟通缺陷和长期的认知缺陷 雄性后代的焦虑显著增加，而雌性后代则没有。我们有证据表明暴露于DEP 显着改变小胶质细胞定植的男性，但不是女性胚胎脑，并结合产前 DEP和MS暴露导致相同脑区小胶质细胞功能的持续变化， 男性。除了它们在大脑的先天免疫防御中的功能外，小胶质细胞还是免疫系统的重要调节因子。 发育过程中的经验依赖性突触重塑。有人提出，小胶质细胞修剪 不适当或弱的突触，而保留适当或强的连接。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， 控制活动依赖性突触重塑的分子途径在脑卒中病理学中的重要性 自闭症重要的是，小鼠中受损的小胶质细胞介导的修剪破坏了功能性脑连接， 社会行为，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 病理生理学因此，这里要测试的具体假设是，小胶质细胞活化是由组合的 环境因素会引起这些细胞异常的突触修剪，导致神经回路 功能障碍和类自闭症行为。

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.