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