Owen Leitzel, a graduate student in the lab of Stefanie Robel, Ph.D. — associate professor in the Department of Cell, Developmental, and Integrative Biology — has been awarded an NIH F31 fellowship to support his research investigating the role of connexin43, or Cx43, in seizure susceptibility after traumatic brain injury.Most epilepsy research has focused on neurons, but astrocytes form large, interconnected networks that help maintain the environment that neurons need to function properly. After a traumatic brain injury, those networks can change, and Leitzel’s work asks whether those changes help make the injured brain more susceptible to seizures.
Leitzel remarked, “Receiving this F31 is an important milestone in my graduate training, and I am grateful for the opportunity it gives me to develop the skills and independence I will need to pursue my own scientific questions throughout my career.”
Understanding astrocytes and Cx43
Astrocytes are star-shaped cells that regulate the environment surrounding neurons. Neighboring astrocytes can be connected by structures called gap junctions which directly connect the interiors of the cells. Cx43 is the main protein that forms these channels. By allowing ions and molecules to pass between astrocytes, these gap junctions help astrocyte networks coordinate functions that support normal neuronal activity.
Leitzel’s previous research has focused on how astrocytes change after a mild traumatic brain injury and how these changes may contribute to abnormal neural activity and seizure susceptibility.
“Our lab previously found that after mild traumatic brain injury, a subset of astrocytes lose several proteins that are important for maintaining a healthy environment around neurons, including Cx43,” said Leitzel.
“At the same time, Cx43 protein levels appear to increase in other astrocytes, suggesting that traumatic brain injury may alter Cx43 in more complex ways than simply increasing or decreasing its expression.”
Leitzel explains that Cx43 proteins assemble to form hemichannels in the cell membrane. When hemichannels on neighboring cells dock with one another, they form gap junctions that allow astrocytes to communicate and function as an interconnected network.
Recent collaborative research involving the Robel lab has helped uncover how Cx43 hemichannels may contribute to seizure susceptibility after traumatic brain injury.
“My F31 builds on that work by focusing on a major function of Cx43: gap junction communication between astrocytes,” said Leitzel. “I am investigating whether the astrocyte network becomes disrupted after injury and whether that disruption contributes to increased seizure susceptibility.”
Specifically, Leitzel will study phosphorylation, a chemical modification that can change how Cx43 behaves and where it is located within a cell. Exactly how phosphorylation affects Cx43 and astrocyte networks after traumatic brain injury remains unclear, and answering that question is a central goal of his F31.
“By experimentally manipulating Cx43 phosphorylation and function, I hope to determine how changes in Cx43 may disrupt astrocyte networks and if preserving the connections in these astrocyte networks can reduce abnormal neuronal excitability after traumatic brain injury.”
Building on collaborative research
As part of this collaborative research, Leitzel and the Robel lab have worked with researchers at Virginia Tech who specialize in Cx43 and connexin biology.
“Their perspective has been especially valuable because they approach Cx43 from a molecular and cell biology background, which, in combination with our expertise in astrocytes, traumatic brain injury, and seizures, has provided a deeper understanding of how Cx43 itself is regulated and how its different functions can change under pathological conditions,” said Leitzel.
This cross-disciplinary collaboration has helped strengthen the questions and experiments Leitzel is using to understand how Cx43 changes after brain injury and whether those changes make the brain more susceptible to seizures.
Looking toward new treatments
By determining whether disrupted astrocyte networks are one of the steps linking brain injury to increased seizure susceptibility, Leitzel’s work could identify specific cellular processes that may eventually become targets for preventing or reducing post-traumatic seizures.
“Seizures and epilepsy can develop after traumatic brain injury, but we still do not fully understand the cellular changes that cause an injured brain to become more susceptible to seizures,” said Leitzel.
“If we can identify a specific mechanism by which traumatic brain injury disrupts communication within astrocyte networks and promotes neuronal hyperexcitability, it could reveal new therapeutic targets for preventing or reducing post-traumatic seizures,” said Leitzel.