Brain inflammation as a child can affect the development of two rare types of cerebellar neurons and could provide an insight into its role in conditions such as autism and schizophrenia.
Researchers found that Purkinje and Golgi neurons were vulnerable to brain inflammation and showed premature disruption in their maturation. The findings in Science Translational Medicine offer a window into how inflammation early in life could act as a risk factor for neurological disorders.
Specifically, it is one of the first studies to show that changes in gene expression during inflammation can lay the foundations for later cellular dysfunction. Researcher Seth Ament, PhD, from the University of Maryland School of Medicine, said that his team looked at the cerebellum because it remains understudied despite being one of the first brain regions to start developing and one of the last to reach maturity.
This area of the brain is classically known for motor control but has also been found to regulate higher cognitive functions involving language processing, sociability, and emotions.
“With the fairly new technology of single nucleus RNA sequencing we could look at the cell level to see changes in the brains,” he explained. UMSOM co-author Margaret McCarthy, PhD added: “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 team examined donated post-mortem brain tissues of 17 children who died when they were between one and five years old.
Of these deaths, eight occurred from conditions that involved inflammation such as viral or bacterial infection or asthma or involved the use of anti-inflammatories around the time of death. A further nine deaths were the result of accidents.
None of the children studied had been diagnosed with a neurological disorder before death, and the two groups were similar in terms of age, gender, ethnicity, and time since death.
The researchers found that inflammation and postnatal cerebellar maturation was associated with extensive overlapping transcriptional changes primarily in Purkinje and Golgi inhibitory neurons.
Immunohistochemical analysis in a subset of samples revealed no change to Purkinje neuron size but signs of increased microglia activation among the children with inflammation. Changes in the expression of genes associated with maturation and inflammation included those implicated in neurodevelopmental disorders.
Further investigations revealed seven temporally specific gene networks in Purkinje neurons and indicated that inflammation could be associated with the premature downregulation of developmental gene expression programs.
“Our results further establish the impact of early life inflammation on cerebellar development and its potential relevance to neurodevelopmental disorders,” the researchers reported.
They added: “We found that close to half of the known high confidence risk genes for autism spectrum disorders (ASD) are members of the same gene co-expression module (M7), which is highly expressed specifically in Purkinje neurons at prenatal and early postnatal timepoints and has decreased expression associated with inflammation.
“This finding reveals the enhanced sensitivity of these genes to perturbations in homeostasis.”
The research forms part of a package of 21 research studies across Science, Science Advances and Science Translational Medicine, from the National Institutes of Health’s BRAIN Initiative Cell Census Network (BICCN) that aim to tackle fundamental questions regarding the brain.