Researchers at the University of Virginia School of Medicine have discovered a previously unknown brain repair process that they hope they can harness and improve to treat seizure-related brain damage.
Common anti-epileptic drugs do not work for about a third of patients with epilepsy, so new and better treatments for such brain damage are needed. UVA discovery identifies a potential avenue, inspired by the brain’s natural immune response.
Using high-powered imaging, the researchers were able to see, for the first time, that immune cells called microglia not only clear damaged material after experimental seizures, but actually appeared to heal damaged neurons.
There has been growing generic support that microglia could be used to ameliorate seizures, but direct, visualized evidence for how they might do so has been lacking. Our results indicate that microglia may not simply remove debris, but provide structural support for neuronal integrity that may have implications even beyond the scope of seizures and epilepsy. “
Ukpong B. Eyo, PhD, Researcher, Department of Neuroscience at UVA, UVA Brain Institute and Center for Brain Immunology and Glia (BIG) at UVA
A surprising response to crises
The new findings come from a collaboration of scientists at AVU, the Mayo Clinic and Rutgers University. They used an advanced imaging technique called two-photon microscopy to examine what happened in the brains of lab mice after severe seizures. What they saw was strange and unexpected.
Rather than just cleaning up the debris, the microglia began to form pockets. These pouches did not engulf the damaged material, as many immune cells do. Instead, they started to tend to swell dendrites – the branches of nerve cells that carry nerve impulses. They weren’t removing, the scientists realized; they seemed to heal.
These strange little pockets – scientists called them “microglial process bags” – stayed for hours. They often shrunk, but they were clearly doing something beneficial because the dendrites they were targeting ended up looking better and healthier than the ones they didn’t.
“We did not find that the microglia ‘ate’ the neural elements in this context,” Eyo said. “On the contrary, we saw a strong correlation between these interactions and a structural resolution of injured neurons suggesting a ‘healing’ process.”
New knowledge about the brain’s immune response is pointing scientists in promising new directions. “While these findings are exciting, there is still a lot to follow. For example, the precise mechanisms that regulate interactions remain to be identified. Additionally, at present, the ‘healing’ function is suggested from the results. Correlational and more definitive studies are needed to certify the nature of the ‘cure,’ said Eyo. ‘If these questions can be answered, they will provide a rationale for developing approaches to improve this process … in input contexts. “
Eyo has already received two grants totaling nearly $ 5 million from the National Institutes of Health to continue his study of microglia. The funding will allow him to study how immune cells help regulate vascular function, which could be important in diseases such as Alzheimer’s disease, and their role in overactive brain disorders such as febrile seizures that can trigger epilepsy.
“With this new funding, we look forward to clarifying the roles of microglia in seizure disorders and vascular function,” he said. “UVA’s continued investment is that neuroscience research provides a suitable framework for our lab’s research. “
The researchers published their findings in the scientific journal Cell reports. The research team consisted of Eyo, Koichiro Haruwaka, Mingshu Mo, Antony Brayan Campos-Salazar, Lingxiao Wang, Xenophon S. Speros IV, Sruchika Sabu, Pingyi Xu and Long-Jun Wu.
The research was funded by National Institutes of Health grants R01NS08627, R01NS112144, and K22N84392. Eyo’s new NIH grants are R01NS119243 and R01NS122782.
University of Virginia Health System
Eyo, UB, et al. (2021) Microglia provide structural resolution to injured dendrites after severe seizures. Cell reports. doi.org/10.1016/j.celrep.2021.1109080.