Q&A with Theo Palmer: Genetics, immunology and autism

Theo Palmer, associate professor of neurosurgery, has long sought to understand how genetic and environmental factors collide to shape brain function.

While research in his lab spans many areas –including development, aging, and injury – the effect of maternal health on the fetal brain has always been a major focus.

Recently the lab identified a genetic mutation that may predispose children for autism by changing the immune system of pregnant women. Graduate student Jenny Hsu sat down with Palmer to talk about this work and how it affects the study and treatment of autism.  

How would you define autism?

Autism or Autism Spectrum Disorder is a set of features that people display, mainly differences in social language and communication. Some people might also have intellectual disabilities, while still others have problems with motor skills or repetitive behaviors. Epilepsy and gastrointestinal disorders are also somewhat common. So autism isn’t just one disorder—it’s a collection of features that are lumped into one diagnosis.

What are some of the known risk factors for autism?

A complex genetic background accounts for up to half the cases. Very few single genes can cause autism in isolation, but 500 or more genes acting together can contribute to autism. Then there are really interesting environmental factors that nobody really understands. For example, the rate of autism is higher in children from older parents with advanced degrees and higher incomes. Exposure to pesticides is also associated with higher rates of autism. But these data come from correlative studies, and we don’t know if the relationship is causal.

Which risk factors does your lab study?

A few studies have shown that the rate of autism is higher in kids whose moms were admitted to a hospital for an infection or mild illness during early pregnancy—viral, fungal, bacterial, or even an episode of allergy or asthma. Because the brain regions most affected in autism develop during early pregnancy, we speculate that a mild genetic risk factor may be exacerbated when people are exposed to a mild environmental risk factor that acts on the same disease pathway early in brain development.

We’re testing this idea in mice. We take mice that have genetic mutations known to increase the risk of autism; make them mildly ill during pregnancy; and then study the separate and combined effects of the mutations and illnesses on the fetal brain.

How do you measure autism in mice?

In kids with autism, we mostly see differences in social interaction. But we also see repetitive behaviors or motions, resistance to novelty or change, and aversion to loud noises. So we look at how much time these mice spend interacting with a stranger mouse or more familiar mouse. We spread marbles out on top of their bedding and watch if they obsessively bury them; put them in an open arena and watch how they move around; and observe whether they startle differently in response to loud sounds.

Do you also look for changes on a cellular level?

That’s getting at the heart of what we’re really interested in. When you stimulate a mild immune response in the mom, you activate signaling molecules called cytokines that recruit immune cells to the site of an infection. Cytokines can travel across the placenta and into the fetal brain, and can damage both organs in various ways. We carefully examine what happens in response to an immune event that doesn’t damage the placenta, versus one that does. This way, we can tease apart the different effects of the genetic risk factors and understand whether the gene or immune effects are acting in the mom, the placenta, or in the fetus.

What is one interesting finding from these experiments?

The first genetic risk factor we studied is a mutation in GABAA, a receptor on both neurons and immune cells. Immune cells use this receptor to control the release of cytokines. When we mutate the GABAA gene in the mom and fetus, her pups do not behave differently. But when we trigger an immune response, the mutation causes her immune cells to release too many cytokines, resulting in dramatic damage to the placenta, and extreme autistic-like behaviors in the pups.

Why did this finding surprise you?

People used to think that autism risk genes only functioned in the brain, so they only studied them in terms of how they operate in the fetal or adult brain. But, in hindsight, it makes sense that a brain gene is not just a brain gene. Our results suggest that some of these genes play multiple roles—in the brain, placenta, and immune system – and some may actually be acting in the mom, not the baby.

What implications does your work have for patients?

The value from the medical perspective is that you might be able to genotype moms and say, “you’re at particularly high risk from this environmental factor.” Then we can either try to avoid exposure, or use drugs to prevent or lessen the effects. In fact, two of our mouse models respond to clinically approved drugs, which completely protect the fetus if given at the same time as the immune challenge.

Our approach may also help us understand other neurological or neuropsychiatric disorders. Attention deficit disorder, learning disabilities, dyslexia, and schizophrenia are all more likely to occur if mom is ill during early pregnancy. Finding synergy between genes and environment, and trying to model which interactions are important, that’s the fun part of what we do.

Jenny Hsu is a 6th year graduate student in the lab of Dr. Julien Sage.