Brain Injury: Increasing the Levels of GAT-3 in Thalamic Astrocytes Can Decrease Susceptibility to Seizures

A team of neuroscientists at the Gladstone Institute of San Francisco has discovered a deep pathway in the brain that makes it resistant to injury thanks to the contribution of astrocytes. The study, published in the journal Science Translational Medicine, suggests that targeting this molecular pathway in the thalamus may block long-term damage that can occur following brain injury.Brain

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In the days and even years following a stroke or head injury, the risk of epilepsy multiplies. The researchers in the study have decoded in mice the key role of astrocytes, the star-shaped brain cells found in the thalamus. They then showed, by analyzing post-mortem human brain tissue, that the same cells identified in mice can be altered in the thalamus of people who have suffered brain injuries or strokes.

A protein in astrocytes may prevent long-term damage

It is true that the thalamus is still underexplored after brain injury or stroke,” says lead author Dr. Jeanne Paz of the Gladstone Institute. The researcher hopes that this is just the beginning of a long line of studies on the central role of this area in resilience to brain injury.

When a serious traumatic brain injury or a stroke occurs, many cells at the site of injury die in minutes. Inflammatory cells and molecules gather and clean up dead cells and molecular waste.

In the thalamus, an area deep in the center of the brain – which may therefore be far from the site of injury –
astrocytes are activated, leading to a cascade of inflammatory changes.

Previous studies by the same team have already shown, in animal models, that astrocyte activation in the thalamus is a common consequence of brain injury. However, astrocytes also play an important role in sustaining neurons and connections and regulating nutrient supply.

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Activation of astrocytes in the thalamus also aids brain recovery. “Astrocytes are so important to the brain that they cannot be ignored in the treatment of brain diseases,” explains lead author Frances Cho, “so we set out to identify and separate the harmful and protective effects of astrocytes.”

Activated thalamic astrocytes contribute to some of the long-term symptoms of brain injury, including an increased risk of seizures and sleep disturbances.

The Study

  • Activation of thalamic astrocytes in healthy animals is sufficient to cause changes in brain activity patterns similar to those seen after injury and to increase the risk of seizures.
  • Activated astrocytes lose a protein called GAT3, which is responsible for regulating levels of an inhibitory neurotransmitter so as a result the neighboring neurons are exposed to an excess of this neurotransmitter, leading to neuronal hyperexcitation and susceptibility to seizures.
  • Increasing GAT3 protein in thalamic astrocytes restores normal neuronal function, prevents neuronal hyperexcitability, and reverses the increased risk of seizures caused by astrocyte activation.
  • These processes are confirmed in mouse models of brain injury: increased levels of GAT3 in thalamic astrocytes in these mice are sufficient to prevent neuronal hyperexcitability and increased risk of seizures and mortality.
  • These processes are then validated on thalamic samples from post-mortem brain biopsies.

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Clinical significance

These activated astrocytes are different in many ways from astrocytes that are not activated, it is therefore surprising that a unique target of GAT3 exists to prevent the consequences of brain injury.

Because these changes in the thalamus occur after the initial brain injury, there is a window of opportunity for clinicians to intervene to stop or reverse this process and prevent the increased risk of seizures and convulsions.

References

Enhancing GAT-3 in thalamic astrocytes promotes resilience to brain injury in rodents

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