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Principal Investigator: Lawrence, David A
Institute Receiving Award Wadsworth Center
Location Menands, NY
Grant Number R01ES025584
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Sep 2016 to 31 Aug 2021
DESCRIPTION (provided by applicant): Although antibodies (Abs) to brain antigens have been implicated in the development of ASD, and the specificities of these Abs are beginning to be identified, there has been no direct quantification of the mechanisms responsible for the behavioral aberrancies associated with ASD. Communication between neurons in different brain regions requires the neurons to establish information delivery circuits with extended arms connecting the neurons located at different distances. Interference with proper connections can affect numerous behaviors as well as normal body functions. This study will utilize brains from mice that have ASD- like behaviors (BTBR strain) and those with normal behavior unless exposed to altered fetomaternal influences from toxicant exposures with HgCl2 and/or diesel exhaust particles (DEP). Prenatal Hg and DEP effects have been reported to induce ASD-like behaviors similar to those of BTBR mice, which have anti-brain Abs and neuroinflammation. These immune activities in the brain are posited to interfere with development of proper neuronal connections. The hypothesis is that environmental toxicants induce a combination of fetal innate immune cell (microglial) activities and maternal Abs to initiate a detrimental neuroinflammatory response in the developing brain. The resultant inflammation and immune interferences with neuronal structures/functions alter synaptic neuronal connections and functions resulting in the ASD-like behaviors of offspring. Microglia are known to influence the development of neuronal circuits, so it is not surprising that toxicants, which can alter immune cell phenotypes, could directly affect the type of microglia developed from yolk sac progenitors, their distribution in the brain, and their functions in the presence of immune complexes (Abs and brain antigens). The common specificities from mouse studies will be used to explore the Ab specificities in newborn blood of children now known to have ASD. In the proposed study, Abs will be assayed in organotypic co-cultures of fetal or neonatal tissue from different brain regions to quantify modulation of “neuronal connectivity”. The brain regions will come from normal untreated mice or from brain regions of the fetuses or neonates from Hg and DEP exposed dams ± the Abs with common specificities of experimental mice and human newborns. By mixing the source of the mouse brain region, we will investigate if the detriment is more with the sprouting or targeted region. The study has short-term and long-term impact on the field of ASD research. The most immediate impact is identification of an “Ab Biosignature of ASD” that could diagnose the ASD phenotype at birth. Another short-term impact would be delineation of the specificities and mode of action of the Abs and microglia that identify ASD-related mechanisms, which in the long-term could aid in determining interventions that might be most appropriate. Identification of the mechanisms detrimental to normal neuronal connectivity and function could assist in the development of therapeutic interventions. The study also will validate the establishment of an experimental model system to screen additional environmental toxicants.
Science Code(s)/Area of Science(s) Primary: 61 - Neurodevelopmental
Publications See publications associated with this Grant.
Program Officer Cindy Lawler
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