A new cell therapy enhanced memory and prevented seizures in mice after traumatic brain injury, researchers from the University of California, Irvine report[1].

The researchers transplanted embryonic progenitor cells capable of generating inhibitory interneurons, a specific type of nerve cell that controls the activity of brain circuits, into the brains of mice with traumatic brain injury. They targeted the hippocampus, a brain region responsible for learning and memory.

“Inhibitory neurons are critically involved in many aspects of memory, and they are extremely vulnerable to dying after a brain injury. While we cannot stop interneurons from dying, it was exciting to find that we can replace them and rebuild their circuits,”

says Robert Hunt, an assistant professor of anatomy and neurobiology at the School of Medicine at the University of California, Irvine, who led the study.

Neuron Migration

The researchers discovered that the transplanted neurons migrated into the injury where they formed new connections with the injured brain cells and thrived long term.

Within a month after treatment, the mice showed signs of memory improvement, such as being able to tell the difference between a box where they had an unpleasant experience from one where they did not. They were able to do this just as well as mice that never had a brain injury.

[caption id=“attachment_101336” align=“aligncenter” width=“700”] MGE transplantation does not alter glial responses to TBI.

(a) Coronal brain sections 125 DAT labeled for GFAP (orange), IBA1 (magenta) and transplanted MGE cells (green). In the ipsilateral hemisphere, there was prominent glial scar surrounding the impact site.

(b) Quantification of GFAP expression in neocortex and hippocampus in sections contralateral and ipsilateral to the injury. Ipsilateral neocortex: **P = 0.007, control vs TBI; **P = 0.009, control vs TBI-MGE; one-way ANOVA with Bonferroni post hoc test; Ipsilateral hippocampus: *P = 0.04, control vs TBI; **P = 0.008, control vs TBI-MGE; one-way ANOVA with Bonferroni post hoc test. n = 4 control mice, n = 3 TBI mice, n = 3 TBI-MGE mice.

(c) Quantification of IBA1 immunostaining in neocortex and hippocampus in sections contralateral and ipsilateral to the injury. Ipsilateral neocortex: *P = 0.03, control vs TBI; *P = 0.03, control vs TBI-MGE; one-way ANOVA with Bonferroni post hoc test.

(d) High resolution images of the boxed region in a labeled for GFAP (orange), IBA1 (magenta) and GFP (green). Transplanted MGE cells did not co-localize with glial markers (n = 3 mice per marker).

Credit: Bingyao Zhu, et al. CC-BY[/caption]

The cell transplants also prevented the mice from developing epilepsy, which affected more than half of the mice not treated with new interneurons.

Traumatic brain injuries affect 2 million Americans each year and causes cell death and inflammation in the brain. People who experience a head injury often suffer from lifelong memory loss and can develop epilepsy.

Interneuron Transplantation Therapy

This is not the first time Hunt and his team has used interneuron transplantation therapy to restore memory in mice. In 2018, the team used a similar approach[2], delivered the same way but to newborn mice, to improve memory of mice with a genetic disorder.

Still, this was an exciting advance for the researchers.

“The idea to regrow neurons that die off after a brain injury is something that neuroscientists have been trying to do for a long time,” Hunt says. “But often, the transplanted cells don’t survive, or they aren’t able to migrate or develop into functional neurons.”

To further test their observations, Hunt and his team silenced the transplanted neurons with a drug, which caused the memory problems to return.

“It was exciting to see the animals’ memory problems come back after we silenced the transplanted cells, because it showed that the new neurons really were the reason for the memory improvement,”

says first author Bingyao Zhu, a junior specialist.

Currently, there are no treatments for people who experience a head injury. If the researchers can replicate the results in humans, it could have a tremendous impact for patients. The next step is to create interneurons from human stem cells.

[1] Bingyao Zhu, Jisu Eom & Robert F. Hunt. Transplanted interneurons improve memory precision after traumatic brain injury. Nat Commun 10, 5156 (2019) doi:10.1038/s41467-019-13170-w

[2] Young J. Kim, et al. Chd2 Is Necessary for Neural Circuit Development and Long-Term Memory. Neuron; Volume 100, Issue 5, p1180-1193.E6, December 05, 2018

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