Retuning Bioelectric Brain Signals In Frog Embryos Reverses Birth Defects

African clawed frog (Xenopus laevis), an animal that's one of the most widely used for developmental, cell, and molecular biology. D. Kucharski K. Kucharska/Shutterstock

Damaged frog embryo brains can be repaired by drugs that spark the recovery of the bioelectric patterns in the embryo, as shown by new research reported in the journal Frontiers in Neuroscience. While the research is still in its early days, it suggests a possible avenue for therapeutic drugs to be used to retune the bioelectrical "blueprint" during embryonic development and treat certain birth defects. 

Scientists led by Tufts University looked to repair the brains of African clawed frog (Xenopus laevis) embryos damaged by nicotine exposure using "ionoceuticals,” drugs that target ion channels that manage the electrical signaling of the brain. 

In a developing embryo, the formation of different tissues and organs is, in part, regulated by bioelectric signals, whereby charged ions move in and out of cells, creating voltage differences across the cell membranes. The researchers describe these bioelectric signals and the varying voltage levels as a kind of “blueprint” that’s used to guide the organization of embryonic development. Nicotine, however, is an agent that can affect the developing brain by draining the contrast of the bioelectrical signals that control brain development. Instead of being a rich and complex map of varying bioelectrical signals, like an image shaded with deep blacks and bright whites, the blueprint becomes muted of range and full of “greys.” 

Image of a normal frog embryo brain (left). Nicotine induced defects in the frog embryo brain (center) can be rescued by transplanting an HCN2 expressing patch on the embryo far from the brain. Treated embryos are observed to have normal brain morphology and function (right). Vaibhav Pai/Tufts University

For this new research, the researchers managed to restore the normal contrast of bioelectrical signals involved in brain development known as HCN2. Using frog tadpoles that had been exposed to nicotine, they used ionoceutical drugs called lamotrigine and gabapentin to foster the recovery of normal bioelectric patterns in the embryo, which led to the repair of structural defects in the brain, along with the restoration of gene expression and brain function.

Previous research has tweaked HCN2 to perform normally using gene therapy, but this new research managed to repair the defects by using small molecule drugs that activated HCN2 channels already present in the embryo. Furthermore, the treatment allows for the restoration of the brain's electrical signal without targeting the specific region that is damaged.

"What was remarkable about the experiments in this study is that when we increased expression of HCN2 at a distance from the brain, in non-neural regions, the defects in the brain were still repaired or prevented," Michael Levin, study author and Vannevar Bush professor of Biology at Tufts University's School of Arts and Sciences, explained in a statement.

"The instructions to build a fully grown animal, including organs as complex as the brain, are distributed among all the cells of the embryo," he added. "These results suggest that we might not have to directly target the damaged region, and we can use drugs instead of genetic manipulation, which opens a lot of opportunities for biomedical deployment." 



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