New research from a team at the University of Maryland School of Medicine (UMSOM) has for the first time shown how inflammation in early childhood can affect brain development and contribute to the risk of autism spectrum disorders (ASD) and schizophrenia. The findings show inflammation can trigger epigenetic changes in brain regions linked to higher cognitive functions and potentially play a role in a variety of neuropsychiatric disorders.
It’s fair to say we couldn’t live without our immune system. This crucial defense system protects the body from a variety of microbial attackers. And inflammation is the front-line response from the immune system when our body faces injury or infection.
The body’s inflammatory response can sometimes be a bit of a blunt instrument, causing collateral damage in its hunt for pathogens. Or even, in cases of chronic autoimmune disease, mistakenly taking out healthy cells triggering long-term illness. We also know that maternal inflammation during pregnancy can affect fetal neurodevelopment. Observational studies have linked viral and bacterial infections during pregnancy to increased risks in children for autism and schizophrenia.
However, it hasn’t been clear whether these inflammatory responses continue to disrupt neurodevelopment across a child’s first few years of life. And we don't know exactly how inflammation could be stifling brain development.
In a first-of-its-kind study led by Seth Ament, from UMSOM’s Institute for Genome Sciences, and Margaret McCarthy, director of the Institute of Neuroscience Discovery, researchers have directly shown how inflammation could be affecting neurodevelopment.
The researchers gathered post-mortem brain tissue from 17 deceased children. Half of the cohort died while experiencing acute inflammation, while the other half died suddenly from accidents. The study focused on epigenetic changes in a part of the brain called the cerebellum.
“We looked at the cerebellum because it is one of the first brain regions to begin developing and one of the last to reach its maturity, but it remains understudied,” Ament explained. “With the fairly new technology of single nucleus RNA sequencing we could look at the cell level to see changes in the brains.”
The findings revealed two specific types of cerebellar neurons were particularly sensitive to inflammation: Golgi and Purkinje neurons. Although these two cell types are relatively rare, Ament says they play critical roles in cognition and behavior.
“During development, Purkinje neurons form synapses connecting the cerebellum to other brain regions involved in cognition or emotional control, while Golgi neurons coordinate communication between cells within the cerebellum,” Ament says. “Disruption of either of these developmental processes could explain how inflammation contributes to conditions like autism spectrum disorders and schizophrenia.”
In the cells exposed to inflammation the researchers detected epigenetic changes that were consistent with the downregulation of developmental gene expression programs. In other words, it seemed like inflammation was stifling cellular maturation in these critical brain regions.
Maureen Cowan, a scientist from the University of Virginia whose research focuses on the effects of neuroinflammation, calls the new study intriguing. Cowan, who didn’t work on this study, points out the tissue samples collected in the inflammatory cohort came from patients experiencing a broad variety of conditions, from meningitis to asthma. But despite this heterogenous cohort there seemed to be a consistent cellular impact, suggesting different sources of inflammation trigger similar effects on the brain.
"What’s most exciting to me about this study is the observation that epigenetic changes seen in neurons during inflammation parallel genetic risk factors for conditions like autism, schizophrenia, and bipolar disorder,” says Cowan. “These results suggest that there are shared molecular signals seen in different types of inflammation that can contribute to underlying neuronal dysfunction in the developing brain."
The study focused on subjects experiencing acute inflammation so it’s unclear whether these findings apply to milder chronic inflammation. Ament does indicate that prior animal studies suggest low-level inflammation can lead to neurological dysfunction, however, it is likely other factors play a role in the ultimate development of conditions such as autism.
“Dr. McCarthy has previously shown that (survivable) inflammation during an equivalent postnatal critical period in rats leads to changes in Purkinje neuron development, as well as social behavior deficits in adulthood,” Ament says. “In humans, it is likely that the effects of inflammation on neurodevelopmental disorders will vary depending on interactions with genetic risk and additional experiences.”
In terms of when a child might be most vulnerable to the effects of inflammation on cerebellum development, Ament says around the age of 12 months is when many of these neuronal changes begin to take hold.
“Our current data suggest that the greatest vulnerability begins when children are one year old,” he explains. “The gene expression patterns that we discovered suggest that many of these developmental processes are complete by the time children are about five years old. However, there is a need to study additional samples from infants and older children to fully delineate these time courses.”
The researchers are cautious to stress inflammation is likely just one causal factor amongst several that contribute to the development of disorders such as ASD and schizophrenia. We know genetics and environment play significant roles in neuropsychiatric disease so a single passing viral infection in a toddler isn’t going to be a sole cause of autism.
Nevertheless, the findings offer some of the first in-human evidence of how inflammation could contribute to dysfunctional brain development. And, according to Cowan, the study is yet more proof of the broader role inflammation can play in neurological disease.
"Beyond this study, we also see that overexuberant immune activation can contribute to neurological disease later in life, like in the case of Alzheimer’s disease,” Cowan says. “Such observations highlight how the immune system must play a balancing act between adequately defending the brain against real threats and causing neurodegeneration."
The new research was published in Science Translational Medicine.
