UC Davis

Substantial research now suggests that immune cells and related signaling molecules are involved in central nervous system (CNS) development, homeostasis, and disease. Neurodevelopmental disorder (NDD) is one such case where individual or familial autoimmunity and dysregulation of immune cell subsets and specific cytokines have been implicated. A particularly salient example being the role of maternal autoantibodies in autism spectrum disorder (ASD), termed maternal autoantibody related (MAR) ASD. The first chapter of this work will provide the necessary background to understand the above topics and information detailed in subsequent chapters.

To increase our understanding of how a peripheral immune challenge during early life may impact CNS immune signaling, Chapter 2 details a set of experiments where rats were injected peripherally with a cocktail of immune stimulants and effects on the CNS were measured. Luminex analysis of serum and brain region-specific cytokine profiles revealed significantly different immune responses in the CNS compared to the periphery. This finding was accompanied by altered brain glial fibrillary acidic protein (GFAP) and allograft inflammatory factor 1 (IBA1) immunoreactivity in a strain- and sex-dependent manner. These results lay the groundwork for future studies examining CNS immune signaling in response to different peripheral stimuli.

Beyond aberrant cytokine signaling, pro-inflammatory stimuli may lead to the production of autoantibodies (aAbs) that could interfere with target protein function. Chapter 3 describes the effects of endogenous aAb exposure using a mouse model of MAR-ASD, where aAbs present in maternal circulation are known to target antigens enriched in the developing brain. To examine this concept, mouse dams were induced to create aAbs to MAR-ASD targets and offspring outcomes were assessed postnatally. Findings support that MAR-ASD aAb exposure results in effects on offspring behavior and brain structure that were sex-specific and suggested network-level desynchronization of regional brain volume. Expanding upon these findings, Chapter 4 details a similar design of MAR-ASD aAb exposure using a rat model. Rats were chosen due to the enhanced behavioral and neuroanatomical complexity of rats. Results broadly corroborated findings observed in MAR-ASD mice providing additional insight regarding regional effects on brain volume by sex. Furthermore, the use of magnetic resonance spectroscopy (MRS) revealed altered levels of several neurometabolites in the cortex of rats supporting a molecular basis for MAR-ASD-induced effects.

Research regarding the influence of immune signaling in the CNS is still limited, the studies included herein provide support for robust CNS cytokine response following peripheral induction and the influence of maternally-transferred autoreactive immunoglobulin G (IgG) on neurodevelopmental trajectory of offspring. Chapter 5 provides further details on the significance of these findings, how they may inform therapeutic intervention clinically, and future studies that will be important to understand potential mechanisms of maternal immune influence on neurodevelopment.