Suffering a stroke or other traumatic brain injury puts a patient at heightened risk for developing seizures for days, and even years after. In a new study, Gladstone Institutes researchers report that cells called astrocytes in the thalamus area of the brain play a significantly active role in seizure susceptibility in mice. Their work also reveals similar findings in human brain tissue.
At the time of a stroke or something similar, many cells at the site of the injury die almost on the spot. The thalamus, which is deep in the brains’ core and potentially far from the site of injury, contains astrocytes that become activated and lead to a chain of inflammatory responses. For this reason, the team believes it should be a prioritized area of study.
“In the aftermath of brain injuries, the thalamus has been relatively understudied compared to other brain regions,” says Jeanna Paz, PhD, an associate investigator at Gladstone and senior author of the new study.
Knowing the role that the thalamus and astrocytes play in inflammation and epilepsy complications, the team wanted to discover if there was a possible way to help the brain recover through their activation instead of cause harm.
“Astrocytes are so important to the brain that you can’t just get rid of them to treat disease,” says Frances Cho, a graduate student at Gladstone and UC San Francisco (UCSF), and first author of the new study. “We needed to determine whether we could separate the damaging actions of activated astrocytes from their protective actions.”
To do this, the team initially tested the consequences of activating thalamic astrocytes in healthy animals. As expected, they found that just activating them was enough to cause altered brain activity in a similar fashion to those seen after injury, and made the mice more prone to seizures. As they examined the molecular components of the activated cells, they discovered that they lost a protein called GAT3, which is responsible for regulating the levels of a specific inhibitory neurotransmitter. Due to this loss, the surrounding neurons were exposed to too much of the neurotransmitter, resulting in hyperexcitability and increased seizure risk.
From this, they noticed that the key point was that the loss of GAT3 was responsible for dysregulation. The researchers wondered if this meant that somehow increasing GAT3 within the cells meant that they could limit the consequences of injury. They collaborated with UCLA researchers to generate a tool that could increase the amount of the protein in the brain. They found their hypothesis to be true. Increasing the amount of GAT3 was indeed able to reduce seizure and mortality risk in mice with brain injuries.
The final test was to see if this could be translated to humans. The researchers obtained three human post-mortem thalamus samples from individuals with no known brain injuries, three from people who suffered a stroke, and four from people with 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,” explains Cho.
Cho and the rest of the team believe that this is a breakthrough finding, opening the door to a range of possible therapeutics that target the thalamus and the astrocytes within it. Since there is some room right after a brain injury, this could allow healthcare professionals to intervene swiftly and stop progression.
“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,” concludes Cho.
The study is published in the journal Science Translational Medicine.