How Brain Inflammation May Cause Neurological Disorders

Severe inflammation in early childhood is a clinically known risk factor for developing autism and schizophrenia. Now, for the first time, scientists have discovered that inflammation alters the development of vulnerable brain cells, and this could have mechanistic links to neurodevelopmental disorders. 

Using single-cell genomics to study the brains of children who died from inflammatory conditions along with those who died from a sudden accident, researchers led a study that found inflammation in early childhood prevents specific neurons in the cerebellum from maturing completely. The cerebellum is a brain region responsible for motor control and higher cognitive functions used in language, social skills, and emotional regulation.

Previous research has shown that babies born with abnormalities of the cerebellum frequently go on to experience neurodevelopmental disorders, and animal models exposed to inflammation before birth also develop these conditions.

“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,” said Seth Ament, Ph.D., IGS scientist who co-led the research with Margaret McCarthy, Ph.D. “With the fairly new technology of single nucleus RNA sequencing we could look at the cell level to see changes in the brains.”

Added Dr. McCarthy: “This has never been done before in this age group and in the context of inflammation. The gene expression in the cerebella of children with inflammation were remarkably consistent.”

The researchers examined donated post-mortem brain tissues of 17 children who died when they were one to five years old, eight from conditions that involved inflammation and nine from accidents. None of the donors had been diagnosed with a neurological disorder prior to death. The two groups were similar in age, gender, race/ethnicity, and time since death. 

The study found that two specific, yet rare types of cerebellar neurons were most vulnerable to brain inflammation — the Golgi and Purkinje neurons. At the single-cell level, these two types of neurons showed premature disruption of their maturation.

“Although rare, Purkinje and Golgi neurons have critical functions,” Dr. Ament said. “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. Disruption of either of these developmental processes could explain how inflammation contributes to conditions like autism spectrum disorders and schizophrenia.”

As with many diseases, both genetics and the environment — in this case, inflammation — likely contribute to the risk of developing these disorders. That’s why it is crucial to understand the roles of specific cells within the brain regions — as well as how they interact with genes to influence brain function — to find treatments for brain disorders, like ASD and schizophrenia, as well as others including dementia, Parkinson’s disease, or substance use disorders.

Sources:

Seth A. Ament, Marcia Cortes-Gutierrez, Brian R. Herb, Evelina Mocci, Carlo Colantuoni, Margaret M. McCarthy. A single-cell genomic atlas for maturation of the human cerebellum during early childhood. Science Translational Medicine, 2023; DOI: 10.1126/scitranslmed.ade1283

University of Maryland School of Medicine. “How brain inflammation in children may cause neurological disorders.” ScienceDaily. ScienceDaily, 12 October 2023. <www.sciencedaily.com/releases/2023/10/231012161729.htm>.

Materials provided by University of Maryland School of Medicine. Original written by Heide Aungst. Note: Content may be edited for style and length.

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