Insights into Tourette Syndrome Brain Mechanisms Revealed by 3D Organoid Models

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Tourette syndrome is a disorder that causes uncontrollable vocal or motor tics. It usually begins in childhood, and it can affect school performance, relationships and quality of living. A Yale team used stem cells to create 3D brain models in a culture plate that mirrored the development of patients’ brains. This revealed mechanisms for why this condition occurs.

Research has shown that TS patients have different basal ganglia – the region of the brain below the cerebral cortex which governs language, and skillful movements – than the general population. The basal neurons in these patients are smaller and have fewer of a certain type of specialized neuron that controls how the basal cells receive and elaborate information coming from the cortex. These are interneurons. They are neurons found only in the central nervous systems and are crucial to controlling inhibition.

The team created organoids that resembled the basal ganglia. These 3D cell configurations modeled the way this portion of brain grew in embryonic development among a cohort TS patients. The models revealed a potential pathophysiology for the disorder. This, the team hopes, could lead to the development of new therapies. The results were published in Molecular Psychiatry, on November 29, 2018.

Flora Vaccarino MD, the Harris Professor at the Yale Child Study Center, and the senior author of this study, says that if we want to understand the origins of disorders such as Tourette syndrome we must study them from the beginning. “Organoids allow us to look back at disease development and examine the mechanisms behind it.”

Tourette Syndrome and Basal Ganglia Differences

The first signs of TS are usually seen in children aged between 5 and 10 and often occur with ADHD and OCD. Involuntary movements like eye blinking, throat cleaning, and vocalizations are common in children with TS. They may temporarily be able suppress their tics but it takes a lot of effort. In severe cases, the tic can lead to self-harming behavior. In over half of cases, the disorder improves with age. Tics become less noticeable and less disruptive. Researchers have found that the disorder is highly heritable but only a few genes are involved.

Vaccarino says that the basal ganglia are responsible for motor programs we do not consciously consider, like speaking. Many of our movements, such as walking or riding a bicycle, are ingrained in us from the time we were children. We do them now without even thinking. These programs are stored within the basal Ganglia.”

If we want to avoid disorders such as Tourette syndrome, then we must study the very first signs of the disease. Organoids allow us to look back in time at disease development.

– Flora Vaccarino, MD

When the development of the base ganglia is not correct, it can lead to abnormal movements such as tics. You’re doing something and suddenly, you feel the need to speak or clear your throat. She says that it doesn’t have anything to do with the movements you are doing. It just pops up.

Image studies show that children and young adults who have TS have slightly smaller basal ganglia. Vaccarino’s group was intrigued and conducted a previous study using post-mortem basal ganglia samples from deceased TS donors who donated their brains to research. The study showed a loss in inhibitory interneurons, which are critical for regulating the way basal ganglia react to cortical signal.

“We think that abnormal movements are caused by cortical stimulation, not being suppressed,” says Vaccarino.

It was still a mystery why these neurons are missing in TS. Researchers did not know if they died later in life, or if perhaps their development was halted altogether. Melanie Brady, Ph.D. a graduate student in Vaccarino’s lab at the time, decided to do an investigation.

Tourette Organoids Reveal Neurological Anomalies

The team recruited 11 controls and five TS patients for their latest study. The team took a sample of skin from each patient and created induced pluripotent cell lines. The neurons of the basal Ganglia can be programmed from pluripotent stem cell lines. It involves growing pluripotent cells into 3D cell assemblies called organoids. These cells then differentiate into neurons, mimicking embryonic growth. Brady says that organoids give us the ability to study multiple cell types simultaneously and better understand the complexity of the brain on a patient specific basis. The basal ganglia neuron development could be compared in organoids from control and TS patients.

The team first wanted to compare the presence of inhibitory interneuron in TS organoids with controls. They searched for specific markers of these neurons using immunocytochemical analysis to visualize proteins and also sequenced the RNA to detect inhibitory interneurons-specific transcripts. Both methods confirmed a reduction in inhibitory interneuron in TS organoids.

“This proves that these neurons were never lost. They failed to be created in the first instance,” says Vaccarino. We saw these cells missing when we followed the organoid’s development from its very beginning.

The progenitor cell that was supposed to become an inhibitory interneuron instead gave rise to other types of cells. This led to an abnormal patterning in the TS Organoids.

The team also looked for possible reasons behind the interneuron deficit and the mispatterning of the basal ganglia. The researchers found that TS stem cells had a reduced response to Sonic Hedgehog morphogen, which is essential for the development and growth of basal ganglias in the brain. Sonic Hedgehog was added to the culture at an early stage to produce basal ganglias organoids. Researchers believe this abnormal response may be linked to the anomalies displayed by TS organoids.

Tic Severity and Abnormalities Appear Related

The study concluded that there was a correlation between the severity of tics and the degree of abnormality in the basal organoids. One of five TS patients had much milder symptoms compared with his cohort. Organoids made from his stem cell showed the least amount of interneurons, and the least obvious mispatterning. This suggests that the organoid’s phenotype could predict the severity in childhood. Brady says that identifying differences in neurobiology at the developmental stage may lead to an earlier diagnosis and new ways to manage the disorder.

The team plans to examine the genetic and epigenetic background of TS patients to understand the role they may play in this abnormal response. Vaccarino is hopeful that the ongoing research of her group could lead to therapeutic interventions. Future drugs could, for example, compensate for the lower number of interneurons found in TS patients’ basal ganglia by increasing their excitability.

“Once you understand why something is happening, you can come up with ways to improve it,” Vaccarino explains.

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