This Autism Speaks Weatherstone fellow is deepening our understanding of how inflammation affects prenatal brain development
Post by neuroscientist Myka Estes, a 2012 Autism Speaks Dennis Weatherstone Predoctoral Fellow. Dr. Estes is continuing her autism research as a postdoc in the neurodevelopment lab of Kimberley McAllister at the University of California, Davis. Her Autism Speaks fellowship supported her early investigations into immune system abnormalities suspected to affect early brain development and predispose to autism.
Over the last five years, it’s become increasingly clear that autism frequently results from a combination of genetic predisposition and environmental risk factors. By environmental factors, scientists mean non-genetic influences such as infection, nutritional deficiency or exposure to a toxic chemical or high levels of pollution during pregnancy.
How might genetic and environmental influences converge to affect early brain development? For one thing, they can both affect our immune system.
That’s where my research comes in. Our lab is investigating the role that the immune system may play in predisposing a child to autism.
The immune system’s most familiar role is to protect us from infection. One of the ways it does so is by producing infection-fighting inflammation. However, inflammation can also produce problems. Autoimmune diseases and allergies are two common examples.
Research by our team and others is revealing disruptions in immunological pathways that may be shared by many people on the autism spectrum. One recent study looked at the activity of more than 30,000 genes in post-mortem brain tissue from people affected by autism.
It found more than 400 genes whose activity tends to be altered in people who have autism. These genes fell into two broad groups. One groups produces proteins involved in forming connections between neurons. The other produces proteins that play important roles immune function.
Our lab is particularly interested in proteins that play both roles: namely, proteins that play important roles in both immune function and brain function. These proteins help activate and regulate the body’s immune system as well influence brain development and function.
We think these proteins – and the genes that control them – may play an important role at the intersection between autism’s genetic and environmental risk factors.
The prenatal window
Our research focuses on the prenatal period because a large body of research has shown that the developing brain is most vulnerable to environmental insults before birth. This may be because the developing immune system interacts most directly with the brain during prenatal development – because the so-called blood-brain barrier has yet to form fully.
If an environmental exposure produces an immune response – as stresses on the body tend to do – that immune response can affect the developing brain in ways that can produce lifelong changes in brain connectivity and function.
Supporting this line of thinking, studies have found that many genes associated with autism are particularly active during fetal development.
Infection and inflammation during pregnancy
In our research, we induce an inflammatory reaction similar to a response to an infection in pregnant lab mice. We focus on pregnancy because epidemiological studies have consistently associated maternal infection during pregnancy with disorders of brain development –including autism – in the child.
As we’ve reported in published papers
, when pregnant mice mount an immune response to an infection, it has a dramatic effect on the brains of their offspring. More specifically, we found half as many connections between the nerve cells in the brains of these pups compared to that in typical mice.
Additionally, we showed that this change in brain connectivity involves one of those versatile proteins vital to both immune and brain function. This molecule is major histocompatibility complex I, or MHC I. On the immune side, it protects the body against infection. During early brain development, it tells neurons when and where to make connections.
Such findings are important because they help us understand how genes interact with non-genetic influences – such as infection during pregnancy – to produce autism.
Our research is the first to look at a gene that, when damaged (mutated), increases autism risk and show that the gene's activity (expression) can likewise be altered by an environmental influence such as infection. This finding suggests that while many genetic and non-genetic risk factors are associated with autism, they may affect the same genes and brain-signaling processes. In other words, there may be many ways – genetic and environmental – to alter a few vital brain processes and, so, produce autism.
If this is true, it raises our hope of developing broadly effective autism medicines – treatments that normalize the same brain pathway regardless of how it was disrupted.
There’s still much to learn about how the nervous and immune systems communicate to create and maintain a healthy brain. Through study of this relationship, we hope to find new ways to design treatments that “calm” or otherwise affect the immune response to protect healthy brain development.