An individual who suffers from a stroke or traumatic brain injury have an increased risk of developing epilepsy, even years after they have occurred.
Researchers at Gladstone Institutes have now discovered that star-shaped cells known as astrocytes in the thalamus play a vital role in making mice with brain injuries more prone to having seizures.
As well as studying mice, the research team also studied human post-mortem brain tissue and discovered that the same cells identified in mice, could be altered in the thalamus of people affected by stroke and brain injuries.
The findings from the study suggest that by targeting a protein in these cells could potentially prevent the long-term damage that follows brain injuries.
Jeanne Paz, PhD, an associate investigator at Gladstone and senior author of the new study said: “In the aftermath of brain injuries, the thalamus has been relatively understudied compared to other brain regions,
I’m hoping this is just the beginning of many new lines of research about how important this region is in determining how we can help the brain be resilient to consequences of injuries.”
During a traumatic brain injury or a stroke, many cells at the site of the injury die, because of this, inflammatory cells and molecules begin to gather in order to clean up the molecule debris and dead cells.
In an area deep in the centre of the brain, the thalamus, that might be far from the site of injury, astrocytes activate, thus leading ti a cascade if inflammatory changes.
Previous studies by the team at Gladstone Institutes have displayed, in rodent subjects, that the activation of astrocytes in the thalamus is a common consequence of traumatic brain injuries.
Astrocytes also play a vital role in supporting neurons, as they help to control their connections and provide them with nutrients.
The researchers in this study wanted to determine if the activation of astrocytes in the thalamus helps the brain to recover, leads to additional damage, or has both positive and negative effects.
A graduate student at Gladstone, Frances Cho who is the first author of the new study, said that: “Astrocytes are so important to the brain that you can’t just get rid of them to treat disease,
We needed to determine whether we could separate the damaging actions of activated astrocytes from their protective actions.”
Along with their collaborators, Paz and Cho hypothesised that activated thalamic astrocytes may play a role in some of the longer-term symptoms of brain injury, which include an increased risk of sleep issues and seizures.
At first the team tested the consequences of activating thalamic astrocytes in healthy animals, from this, they found that by activating the star-shaped cells was enough to cause altered patterns of activity in the brain like that that is seen after injury, which made the mice susceptible to seizures.
The researchers then analysed the molecular properties of the activated astrocytes in collaboration with Anna Molofsky’s, MD, PhD, team at UC San Francisco, they found that these cells lost a protein known as GAT3.
This protein is responsible for regulating the levels of a specific inhibitory neurotransmitter molecule.
As a result of activating the astrocytes, the neighbouring neurons were exposed to too much of the neurotransmitter, which lead to neuronal hyper excitability and susceptibility to seizures.
Jeanne Paz said: “We wondered, if the loss of GAT3 in thalamic astrocytes caused neuronal dysfunction, could boosting the level of this protein solve the problem and restore the neurons’ function?”
In order to answer this question, the team collaborated with Baljit S. Khakh, PhD, and his group at UCLA who developed a tool to increase GAT3 specifically in astrocytes.
They discovered that increased levels of GAT3 in thalamic astrocytes were enough to prevent neuronal hyperexcitability and increased seizure risk cause by the activated astrocytes.
The next step took by the researching team was to test whether the results held true in mice with brain injuries. They found that increasing the levels of the GAT3 protein in the thalamic astrocytes of these mice also reduced seizure risk and the rate of mortality.
Frances Cho said: “These activated astrocytes are quite different in many ways than astrocytes that are not activated, so it was surprising we could pinpoint a single molecular change that we could target to prevent the consequences of brain injury.”
Though samples of human thalamus are rarely collected in post-mortem brain biopsies, through collaboration with Eleonora Aronica, MD, PhD and her team at the University of Amsterdam, the researching team were able to obtain a small collection of samples.
Three samples were from individuals without any known brain injuries, three were from those who had suffered from a stroke and four were from individuals who had a traumatic brain injury.
“The post-mortem brains with stroke and traumatic brain injury seemed to have lower levels of GAT3 in their thalamic astrocytes, just as we had seen in the mouse model,”
“We hope that with increased attention to the thalamus, it will become more routine to collect thalamus samples from post-mortem biopsies in the future.” Said Cho
The researching team are hopeful that they can continue to collect longer-term data on both mice and humans to study the time course of astrocyte activation in the thalamus after brain injury.
“Since these changes to the thalamus occur after the initial brain injury, there is a window of time in which clinicians might be able to intervene to stop or reverse them—and prevent the increased risk of developing epilepsy,” said Paz.
