Inflammation in childhood has been linked to neurodevelopmental diseases such as autism spectrum disorders (ASDs) and schizophrenia. Much research has been conducted on the effects of inflammatory insults on developing fetuses, but significantly less is known about the effects of postnatal inflammation on the cerebellum, which is required for motor control and cognitive processing. Â
Researchers have discovered evidence suggesting the cerebellum is engaged in higher-level cognitive tasks like as language comprehension, social awareness, and emotional regulation, while it was previously primarily connected with motor control. The cerebellum does not stop developing after birth; it achieves full size by early adolescence.
Complex feedback loops exist within the neuronal circuitry of the brain, including Purkinje neurons, Golgi neurons, and microglia. Researchers also discovered that Purkinje neurons are more vulnerable to injury during the early stages of postnatal cerebellar development, a previously unknown time period. Sensitivity mediated by prostaglandin-induced estrogen production is one mechanism that may contribute to the dysregulation found in neurodevelopmental disorders. Â
Single-cell transcriptome patterns were compared in children with and without inflammation in their postmortem cerebella. In the cerebellum of inflamed mice, consistent and suggestive patterns of early down-regulation of developmental gene expression programs were seen, which may explain the higher risk of neurodevelopmental problems. Â
In response to inflammation, Golgi neurons, Purkinje neurons, and microglia have been shown to experience significant transcriptional changes. Golgi neurons were found to be significantly injured, raising concerns about possible subtle or context-dependent learning impairments because they are critical for temporal learning and plasticity.
Purkinje neurons were also affected significantly due to their position as the cerebellum’s primary output source. The study addressed various limitations, including sample-to-sample variance in tissue conditions and inflammatory triggers. Despite these limitations, the study found significant uniformity in the transcriptional consequences of inflammation across children who died. Â
The discovery of gene coexpression modules linked to inflammation-related transcriptional alterations in Purkinje neurons has given light on the complicated genetics that underpin ASDs. This work illustrates the convergent effects of genetic and environmental perturbations such as inflammation by insinuating a role for cerebellar neuron growth in the genesis of neurodevelopmental disorders. Â
The authors recognize that more research into the effects of inflammation on neuronal subtypes in other brain areas is needed, but they stress the cerebellum as the primary focus of their work. The findings highlight the need of thinking about different parts of the brain at different stages of development in order to adequately comprehend the numerous reasons of risk for developmental neurological and neuropsychiatric diseases. Â
Journal Reference Â
Ament, S. A., Cortes-Gutierrez, M., Herb, B. R., Mocci, E., Colantuoni, C., & McCarthy, M. M. (2023). Science Translational Medicine, 15(721). doi:10.1126/scitranslmed.ade1283Â
