How brain cells are affected by Tourette syndrome

US researchers have conducted a cell-by-cell analysis of brain tissue from individuals with Tourette syndrome, pinpointing exactly which cells are perturbed and how they malfunction. Their work provides unprecedented insights into the interplay of different brain cell types in Tourette syndrome, suggesting new therapeutic directions. It has been published in the journal Biological Psychiatry.

Tourette syndrome affects as many as one in 150 children. Its primary symptoms are motor and vocal tics, such as eye-blinking or throat clearing that are performed out of context and in a repetitive fashion. Current treatments do not address the underlying causes of the condition.

“While previous research using brain imaging has shown that the deep brain nuclei, the caudate/putamen, that are primarily involved in the control of movement programs, are smaller in people with Tourette syndrome, and our prior studies have found a decrease in interneurons in the basal ganglia region, we lacked a comprehensive understanding of exactly how different cell types in these brain regions are affected by the condition,” noted lead investigator Dr Flora M Vaccarino, from the Child Study Center and Department of Neuroscience at Yale University, Yale Stem Cell Center, and Yale’s Kavli Institute for Neuroscience.

The research team analysed brain tissue samples from six individuals who had severe Tourette syndrome and six matched control subjects without the condition. Using cutting-edge technology that enables the study of individual brain cells, they examined the genes that were expressed in each cell type and the regulatory elements that control gene activity. Advanced single-cell analysis techniques revealed three key changes in the brains of individuals with Tourette syndrome:

• There were about 50% fewer interneurons (specialised brain cells that help regulate the pace of brain electrical activity) in the caudate/putamen region within the basal ganglia, which is crucial for controlling movement. These interneurons normally help down-regulate neuronal activity, and their loss may explain why individuals with Tourette syndrome experience difficulty controlling movements and vocalisations.
• The medium spiny neurons, which are the main long-range projection neurons in this brain region, showed signs of metabolic stress, with decreased activity in mitochondrial genes that control cellular energy production.
• The immune cells of the brain (microglia) showed increased inflammatory activity, and this inflammatory response was directly correlated with the metabolic stress in the medium spiny neurons. This unexpected relationship suggests these cells are communicating in ways that have not been previously recognised in Tourette syndrome.
   

Together, these findings create a pattern that may explain why individuals with Tourette syndrome experience involuntary movements and vocalisations.

“We found evidence suggesting that these changes in gene activity may be caused by alterations in the regulatory elements that control gene expression, providing new insights into how Tourette syndrome develops and new directions for future research,” said co-lead author Dr Yifan Wang, from the Center for Individualized Medicine at the Mayo Clinic. “These findings suggest that the disease may not be caused by defective genes, but rather by improperly switching them on or off during development and lifetime.”

Co-lead author Dr Liana Fasching, from the Child Study Center, added, “What makes this research particularly compelling is that despite Tourette syndrome having one of the highest familial recurrence rates among complex neuropsychiatric disorders, large genetic studies have identified only a few risk genes. This suggested to us that we needed to look more deeply at the actual brain tissue to better understand what’s happening at a cellular and molecular level.”

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