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.

Public Health Relevance

Multiple prenatal/maternal environmental toxins and exposures have been linked to human autism spectrum disorders (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 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. If successful, these studies will establish a causal link between prenatal environmental stressors and neural circuit dysfunction in mice analogous to existing datasets in humans with ASD, and will provide a mechanism and specific signaling pathway by which environmental stimuli can lead to abnormal neural development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
7R01ES025549-04
Application #
9772462
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lawler, Cindy P
Project Start
2016-09-30
Project End
2021-08-31
Budget Start
2019-06-27
Budget End
2020-08-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Duke University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Hultman, Rainbo; Ulrich, Kyle; Sachs, Benjamin D et al. (2018) Brain-wide Electrical Spatiotemporal Dynamics Encode Depression Vulnerability. Cell 173:166-180.e14
Edlow, Andrea G; Glass, Ruthy M; Smith, Caroline J et al. (2018) Placental Macrophages: A Window Into Fetal Microglial Function in Maternal Obesity. Int J Dev Neurosci :
Bordt, Evan A; Smith, Caroline J; Demarest, Tyler G et al. (2018) Mitochondria, Oxytocin, and Vasopressin: Unfolding the Inflammatory Protein Response. Neurotox Res :
Bilbo, Staci D; Block, Carina L; Bolton, Jessica L et al. (2018) Beyond infection - Maternal immune activation by environmental factors, microglial development, and relevance for autism spectrum disorders. Exp Neurol 299:241-251
Bolton, Jessica L; Marinero, Steven; Hassanzadeh, Tania et al. (2017) Gestational Exposure to Air Pollution Alters Cortical Volume, Microglial Morphology, and Microglia-Neuron Interactions in a Sex-Specific Manner. Front Synaptic Neurosci 9:10
Allen, Nicola J; Eroglu, Cagla (2017) Cell Biology of Astrocyte-Synapse Interactions. Neuron 96:697-708
Hanamsagar, Richa; Bilbo, Staci D (2017) Environment matters: microglia function and dysfunction in a changing world. Curr Opin Neurobiol 47:146-155
Bilbo, Staci D (2017) Sex differences in microglial appetites during development: Inferences and implications. Brain Behav Immun 64:9-10