To find out if Gadd45b is required for new brain-cell growth, the research team made mice lacking the Gadd45b gene and tested their ability to generate new brain cells after ECT. They injected the mice with a dye that marks new cells and three days after ECT examined the number of new cells containing that dye in brains from mice with and without the Gdd45b gene. They found that while normal brains showed a 140 percent increase in cell number after ECT, brains lacking Gadd45b only showed a 40 percent increase.
"The question then was, How does Gadd45b do this?" says Song. "It's been controversial that Gadd45b can promote epigenetic changes like global DNA demethylation, but we show that it can promote demethylation of certain genes."
The chemical methyl group, when attached to DNA near genes, can turn those genes off. This so-called epigenetic change is thought to silence genes a cell doesn't use.
By dissecting mature neurons from normal mouse brains and looking for the presence of methyl groups at certain genes known to promote cell growth, the researchers found that after ECT, these genes became demethylated.
However, doing the same thing with mice lacking Gadd45b resulted in no demethylation, suggesting to the team that Gadd45b is indeed required for demethylation.
"We're really excited about thisit's the first time we've seen dynamic epigenetic DNA changes in response to brain activity," says Song.
"Now that we have the mice lacking Gadd45b, our next goal is to see if these mice have problems with learning and memory and how Gadd45b specifically promotes the demethylation to lead to these long-term changes in the brain."
|Contact: Audrey Huang|
Johns Hopkins Medical Institutions