Pathways deep in the brain make it resilient after injury

SAN FRANCISCO, CA—For days, and even years, after a person has suffered a stroke or traumatic brain injury, they have an increased risk of developing epilepsy. Now, researchers at the Gladstone Institutes have found that star-shaped cells called astrocytes in the thalamus play a key role in making mice with brain injuries susceptible to seizures.

The team also analyzed human post-mortem brain tissue and showed that the same cells identified in mice might change in the thalamus of people affected by brain injury and stroke. The findings, published in the journal Science Translational Medicine, suggest that targeting proteins in these cells can prevent long-term damage that follows brain injury.

“After brain injury, the thalamus is relatively under-studied compared to other brain regions,” says Jeanne Paz, PhD, an associate researcher at Gladstone and senior author of the new study. “I hope this is just the start of a lot of new research into how important this region is in determining how we can help the brain become resilient to the consequences of injury.”

An Inflammatory Cascade Deep In The Brain

At the time of a stroke or traumatic brain injury, many of the cells at the site of the injury die immediately. Inflammatory cells and molecules begin to gather, clearing away dead cells and molecular debris. In the thalamus, an area deep in the center of the brain that may be far from the site of injury, cells called astrocytes become activated, causing a series of inflammatory changes.

Previous studies from the team have shown, in rodent models, that astrocyte activation in the thalamus is a common consequence of brain injury. However, astrocytes also play key roles that support neurons, including controlling their connections and providing them with nutrition.

In this study, scientists wanted to determine whether activation of astrocytes in the thalamus helps the brain recover, causes additional damage, or has both positive and negative effects.

“Astrocytes are so important to the brain that you can’t just throw them away to treat disease,” said Frances Cho, a graduate student at Gladstone and UC San Francisco (UCSF), and first author of the new study. “We need to determine if we can separate the damaging actions of activated astrocytes from their protective actions.”

Focus on the Thalamus

Paz, Cho, and their collaborators hypothesized that activated thalamic astrocytes may play a role in several long-term symptoms of brain injury—including an increased risk of seizures and sleep problems. So, rather than studying mice with brain injury, the team initially tested the consequences of thalamic astrocyte activation in healthy animals. They found that activating thalamic astrocytes alone was sufficient to cause changes in brain activity patterns similar to those seen after injury, and to make the mice susceptible to seizures.

When the researchers then analyzed the molecular properties of activated astrocytes, in collaboration with the team of Anna Molofsky, MD, PhD, at UCSF, they found that these cells were missing a protein called GAT3, which is responsible for regulating certain levels. inhibitory neurotransmitter molecules. As a result, neighboring neurons are exposed to too many neurotransmitters, which results in neuronal hyperexcitability and susceptibility to seizures.

“We wondered if loss of GAT3 in thalamic astrocytes causes neuronal dysfunction, could increasing levels of this protein solve the problem and restore neuron function?” said Paz, who is also a professor at UCSF.

To answer this question, the team collaborated with Baljit S. Khakh, PhD, and his group at UCLA who have developed a tool to enhance GAT3 specifically in astrocytes. Remarkably, increased levels of GAT3 particularly in thalamic astrocytes were sufficient to prevent neuronal hyperexcitability and increase the risk of seizures induced by activated astrocytes.

The team next tested whether the results were correct in mice with brain injury. Elevated levels of GAT3 in thalamic astrocytes of these mice also reduced the risk of seizures and mortality rates.

“These activated astrocytes are very different in many ways than inactivated astrocytes, so surprisingly we were able to pinpoint one molecular change that we could target to prevent the consequences of brain injury,” Cho said.

Potential Therapy

Human thalamic samples are rarely collected during post-mortem brain biopsies. However, in collaboration with Eleonora Aronica, MD, PhD, and her group at the University of Amsterdam, the researchers were able to obtain a small number of post-mortem thalamic samples — three from individuals with no known brain injury, three from people who had had a stroke, and four from individuals who had had a stroke. of people with traumatic brain injury.

“Post-mortem brains with stroke and traumatic brain injury appear to have lower levels of GAT3 in their thalamic astrocytes, as we have seen in mouse models,” Cho said. “We hope that with increased attention to the thalamus, it will become more routine to collect thalamic samples from post-mortem biopsies in the future.”

The researchers hope to continue to collect long-term data in mice and humans to study the timing of astrocyte activation in the thalamus after brain injury.

“Because these changes to the thalamus occur after the initial brain injury, there is a time window in which doctors may be able to intervene to stop or reverse them—and prevent an increased risk of developing epilepsy,” says Paz.

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