Evidence suggests many neurological disorders emerge when normal neurodevelopmental trajectories are disrupted, i.e. when circuits or cells do not reach their fully mature state. Microglia play a critical role in normal neurodevelopment and are hypothesized to contribute to brain disease. We used whole transcriptome profiling with Next Generation sequencing of purified developing microglia to identify a microglial developmental gene expression program involving thousands of genes whose expression levels change monotonically (up or down) across development. Importantly, the gene expression program was delayed in males relative to females and exposure of adult male mice to LPS, a potent immune activator, accelerated microglial development in males. Next, a microglial developmental index (MDI) generated from gene expression patterns obtained from purified mouse microglia, was applied to human brain transcriptome datasets to test the hypothesis that variability in microglial development is associated with human diseases such as Alzheimer’s and autism where microglia have been suggested to play a role. MDI was significantly increased in both Alzheimer’s Disease and in autism, suggesting that accelerated microglial development may contribute to neuropathology. In conclusion, we identified a microglia-specific gene expression program in mice that was used to create a microglia developmental index, which was applied to human datasets containing heterogeneous cell types to reveal differences between healthy and diseased brain samples, and between males and females. This powerful tool has wide ranging applicability to examine microglial development within the context of disease and in response to other variables such as stress and pharmacological treatments.

Several neurological conditions are associated with sex differences in prevalence or outcome. For example, autism predominantly affects boys, depression is more common in women, Parkinson's disease more common in men, and Multiple sclerosis in women. In the case of stroke, women have a less favorable outcome and suffer from a more precipitous drop in health status compared to men. As a result, treatment of such diseases is difficult and yields variable results. Despite this, sex is rarely considered when making treatment decisions. The mechanisms underlying sex differences in disease progression are not well understood, however a strong link exists between different inflammation states of men and women and their propensity to develop certain diseases. As neuroinflammation is an important component of pathophysiology in many neurological conditions, it can be speculated that any changes in the state of inflammation in the brain during normal development can potentially lead to an increase in susceptibility to neurological and neurodegenerative diseases. Microglia play a crucial role in onset and modulation of inflammation and thus sex differences in microglial function could explain, at least in part, differences observed in susceptibilities and outcomes of neurological disorders in men and women. Understanding the mechanisms behind sex differences could help develop more targeted therapy with higher success rate, especially in diseases where sex differences are most prominent.

Immune molecules such as cytokines and chemokines and the cells that produce them within the brain, notably microglia, are critical for normal brain development. This recognition has in recent years led to the working hypothesis that inflammatory events during pregnancy, e.g. in response to infection, may disrupt the normal expression of immune molecules during critical stages of neural development and thereby contribute to the risk for neurodevelopmental disorders such as autism spectrum disorder (ASD). This hypothesis has in large part been shepherded by the work of Dr. Paul Patterson and colleagues, which has elegantly demonstrated that a single viral infection or injection of a viral mimetic to pregnant mice significantly and persistently impacts offspring immune and nervous system function, changes that underlie ASD-like behavioral dysfunction including social and communication deficits. Subsequent studies by many labs – in humans and in non-human animal models - have supported the hypothesis that ongoing disrupted immune molecule expression and/or neuroinflammation contributes to at least a significant subset of ASD. The heterogeneous clinical and biological phenotypes observed in ASD strongly suggest that in genetically susceptible individuals, environmental risk factors combine or synergize to create a tipping or threshold point for dysfunction. Importantly, animal studies showing a link between maternal immune activation (MIA) and ASD-like outcomes in offspring involve different species and diverse environmental factors associated with ASD in humans, beyond infection, including toxin exposures, maternal stress, and maternal obesity, all of which impact inflammatory or immune pathways. The goal of this review is to highlight the broader implications of Dr. Patterson's work for the field of autism, with a focus on the impact that MIA by diverse environmental factors has on fetal brain development, immune system development, and the pathophysiology of ASD.