Biology subjects

Van de Water, J.

Publications and source records attributed to Van de Water, J..

4 recordsLinked to original sources

bioRxiv2020

Maternal immune activation during pregnancy alters early neurobehavioral development in nonhuman primate offspring

BackgroundHuman epidemiologic studies have implicated exposure to infectious or inflammatory insults during gestation in the etiology of neurodevelopmental disorders. Rodent models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant brain and behavior development in offspring. The nonhuman primate MIA model provides an opportunity to maximize the translational utility of this model in a species more closely related to humans. MethodsHere we evaluate the effects of MIA on brain and behavioral development in the rhesus monkey (Macaca mulatta). A modified form of the viral mimic, Polyinosinic-polycytidylic acid (PolyIC), was delivered to pregnant rhesus monkeys (n=14) in the late first trimester to stimulate a maternal immune response. Control dams received saline injections at the same gestational time points (n=10) or were untreated (n=4). ResultsMIA-treated dams exhibited a strong immune response as indexed by transient increases in sickness behavior, temperature and inflammatory cytokines. MIA-exposed offspring developed species typical milestones and demonstrate subtle changes in early in social development. However, magnetic resonance imaging demonstrated significant gray matter volume reductions in prefrontal and frontal cortices at 6, 12 and 24 months of age. ConclusionsThese findings provide new insights into the emergence of neuropathology in MIA-exposed primates and have implications for the pathophysiology of human psychiatric disorders associated with maternal gestational infection.

neuroscience↗

bioRxiv2020

A temporal map of maternal immune activation-induced changes reveals a shift in neurodevelopmental timing and perturbed cortical development in mice.

BackgroundEnvironmental insults that activate the maternal immune system are potent primers of developmental neuropathology and maternal immune activation (MIA) has emerged as a risk factor for neurodevelopmental and psychiatric disorders. Animal models of MIA provide an opportunity to identify molecular pathways that initiate disease processes and lead to neuropathology and behavioral deficits in offspring. MIA-induced behaviors are accompanied by anatomical and neurochemical alterations in adult offspring that parallel those seen in affected human populations. MethodsWe performed transcriptional profiling and neuroanatomical characterization in a time course across mouse embryonic cortical development, following MIA via single injection of the viral mimic polyinosinic:polycytidylic acid (polyI:C) at E12.5. Transcriptional changes identified in the cortex of MIA offspring at E17.5 were validated and mapped to cortical neuroanatomy and cell types via protein analysis and immunohistochemistry. ResultsMIA induced strong transcriptomic signatures, including induction of genes associated with hypoxia, immune signaling, and angiogenesis. The acute response identified 6h after the MIA insult was followed by changes in proliferation, neuronal and glial differentiation, and cortical lamination that emerged at E14.5 and peaked at E17.5. Decreased numbers of proliferative cell types in germinal zones and alterations in neuronal and glial cell types across cortical lamina were identified in the MIA-exposed cortex. ConclusionsMIA-induced transcriptomic signatures in fetal offspring overlap significantly with perturbations identified in neurodevelopmental disorders (NDDs), and provide novel insights into alterations in molecular and developmental timing processes linking MIA and neuropathology, potentially revealing new targets for development of novel approaches for earlier diagnosis and treatment of these disorders.

neuroscience↗

bioRxiv2020

Alterations in retrotransposition, synaptic connectivity, and myelination implicated by transcriptomic changes following maternal immune activation in non-human primates

BackgroundMaternal immune activation (MIA) is a proposed risk factor for multiple neurodevelopmental and psychiatric disorders, including schizophrenia. However, the molecular and neurobiological mechanisms through which MIA imparts risk for these disorders remain poorly understood. A recently developed nonhuman primate model of exposure to the viral mimic poly:ICLC during pregnancy shows abnormal social and repetitive behaviors and elevated striatal dopamine, a molecular hallmark of human psychosis, providing an unprecedented opportunity for mechanistic dissection. MethodsWe performed RNA-sequencing across four psychiatrically-relevant brain regions (prefrontal cortex, anterior cingulate, hippocampus, and primary visual cortex) from 3.5-4-year old male MIA-exposed and control offspring--an age comparable to mid adolescence in humans. ResultsWe identify 266 unique genes differentially expressed (DE) in at least one brain region with the greatest number observed in hippocampus. Co-expression networks identified region-specific alterations in synaptic signaling and oligodendrocytes. Across regions, we observed temporal and regional differences, but transcriptomic changes were largely similar across 1st or 2nd trimester MIA exposures, including for the top DE genes--PIWIL2 and MGARP. In addition to PIWIL2, several other known regulators of retrotransposition, as well as endogenous transposable elements were dysregulated in MIA offspring. ConclusionsTogether, these results begin to elucidate the brain-level molecular mechanisms through which MIA may impart risk for psychiatric disease.

neuroscience↗

bioRxiv2019

Enhancing rigor and reproducibility in maternal immune activation models: practical considerations and predicting resilience and susceptibility using baseline immune responsiveness before pregnancy

Despite the potential of rodent models of maternal immune activation (MIA) to identify new biomarkers and therapeutic interventions for a range of psychiatric disorders, their value is currently limited by issues of scientific rigor and reproducibility. Here, we report three sources of variability--the immunogenicity of the poly(I:C), the baseline immune responsiveness (BIR) of the females prior to pregnancy, and differences in immune responses in C57/B6 dams across vendors. Similar to the variable effects of human maternal infection, MIA in mice does not cause disease-related phenotypes in all offspring and the magnitude and type of maternal response, determined by a combination of poly(I:C) dose and BIR, predicts offspring outcome. Together, our results provide recommendations for optimization of MIA protocols to enhance rigor and reproducibility and reveal new factors that drive susceptibility of some pregnancies and resilience of others to MIA-induced abnormalities in offspring.

neuroscience↗