Although antibodies (Abs) to brain antigens have been implicated in the development of ASD, and thespecificities of these Abs are beginning to be identified, there has been no direct quantification of themechanisms responsible for the behavioral aberrancies associated with ASD. Communication betweenneurons in different brain regions requires the neurons to establish information delivery circuits with extendedarms connecting the neurons located at different distances. Interference with proper connections can affectnumerous 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 influencesfrom toxicant exposures with HgCl2 and/or diesel exhaust particles (DEP). Prenatal Hg and DEP effects havebeen reported to induce ASD-like behaviors similar to those of BTBR mice, which have anti-brain Abs andneuroinflammation. These immune activities in the brain are posited to interfere with development of properneuronal connections. The hypothesis is that environmental toxicants induce a combination of fetal innateimmune cell (microglial) activities and maternal Abs to initiate a detrimental neuroinflammatory response in thedeveloping brain. The resultant inflammation and immune interferences with neuronal structures/functions altersynaptic neuronal connections and functions resulting in the ASD-like behaviors of offspring. Microglia areknown to influence the development of neuronal circuits, so it is not surprising that toxicants, which can alterimmune cell phenotypes, could directly affect the type of microglia developed from yolk sac progenitors, theirdistribution 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 ofchildren now known to have ASD. In the proposed study, Abs will be assayed in organotypic co-cultures offetal or neonatal tissue from different brain regions to quantify modulation of “neuronal connectivity”. The brainregions will come from normal untreated mice or from brain regions of the fetuses or neonates from Hg andDEP exposed dams ± the Abs with common specificities of experimental mice and human newborns. Bymixing the source of the mouse brain region, we will investigate if the detriment is more with the sprouting ortargeted region. The study has short-term and long-term impact on the field of ASD research. The mostimmediate impact is identification of an “Ab Biosignature of ASD” that could diagnose the ASD phenotype atbirth. Another short-term impact would be delineation of the specificities and mode of action of the Abs andmicroglia that identify ASD-related mechanisms, which in the long-term could aid in determining interventionsthat might be most appropriate. Identification of the mechanisms detrimental to normal neuronal connectivityand function could assist in the development of therapeutic interventions. The study also will validate theestablishment of an experimental model system to screen additional environmental toxicants.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
