ABSTRACT Maternal immune activation (MIA) during prenatal or postnatal development significantly increases the risk for offspring neurodevelopmental disorders (NDDs) later in life. Growing evidence suggest that regardless of the MIA stimuli (infectious or environmental), offspring exhibit an enhanced risk for lifelong neuropathology defects ranging from reduced brain volume to alterations in neurocircuit organization. The brain extracellular matrix- containing chondroitin and dermatan sulfate-glycosaminoglycans (CS/DS-GAGs) are key regulators of brain development and can be biochemically altered by neuroimmune responses. Defects in CS/DS-GAG abundance and/or sulfation patterning (4S (CS-A), 2S4S (CS-B/DS), 6S (CS-C), 2S6S (CS-D), 4S6S (CS-E), 0S (CS-O)) result in the manifestation of similar neuropsychiatric behaviors as reported in offspring affected by MIA, but whether and how MIA affects offspring brain matrix is unknown. By employing a novel laser capture microdissection coupled mass spectrometry methodology (LMD-LC-MS/MS), our Preliminary Data provide the first evidence for inter- and intra-regional differences in CS/DS-GAG sulfation pattern differences throughout the developing mouse and non-human primate (NHP) brain. Specifically, the hippocampus exhibits a significant increase in both developmental 6S (CS-C) and 2S6S (CS-D) isomers compared to the cortex, implying that the hippocampus remains developmentally plastic long after the maturation of adjacent regions. Moreover, we show that infectious Zika virus MIA during gestation in NHPs decreases the abundance of the developmental 2S6S (CS-D) axonal growth factor attractant isomer in the hippocampus, suggesting stunted neurocircuit formation after infectious MIA, while the non-infectious maternal high fat diet (mHFD) MIA during lactation in mice decreases the abundance of the developmental 6S (CS-C) plasticity isomer in the hippocampus, suggested accelerated early maturation of hippocampal neurocircuits in response to non-infectious MIA. The implication that both infectious and non-infectious MIA insults influence the spatiotemporal regulation of brain CS/DS-GAG sulfation patterns fits a global interconnecting theory linking a range of MIA insults with changes in offspring brain neurodevelopment through re-coding of CS/DS-GAGs. From these results, we propose to 1) determine how MIA exposure affects spatiotemporal expression of offspring CS/DS-GAGs and link these changes to NDDs later in life, 2) mechanistically investigate how these MIA-induced changes in offspring CS/DS-GAGs influence glycan- protein interactions involved in neurodevelopment, and 3) engineer a state-of-the-art nanopore sequencing technology capable of single-molecule sequencing of biological CS/DS-GAGs to discover glycan-protein binding elements. This multidisciplinary proposal has important translational potential to clarify how MIA exposure leads to neuropsychiatric illness through changes in CS/DS-GAG sulfation patterning during childhood neurodevelopment and provides valuable targets in the prevention and treatment of mental health diseases.

Maternal immune activation (MIA) is a primer for long-term neuropsychiatric consequences in offspring, although the exact mechanisms underlying offspring neurodevelopmental defects resulting from these maternal immune insults are unknown. Here, we provide evidence that MIA-induced changes in the developing offspring’s extracellular chondroitin and dermatan sulfate glycosaminoglycan (CS/DS-GAG) sulfation patterning, which are key regulator of axonal guidance and synaptogenesis during neurodevelopment, may result in developmental defects that predispose the offspring to mental health disorders in the adult, and studies outlined within this proposal aim to further investigate this possibility.