by Sarah Webb
CDK5 plays a critical role in integrating new neurons into the adult brain
Stem cells in the hippocampus continue to produce new neurons throughout our lives. But the birth of these neurons is not enough: they have to both reach their appropriate location and integrate into the neural circuitry.
A team led by Fred Gage at the Salk Institute in La Jolla, California, has demonstrated that cells with low levels of cyclin-dependent kinase 5 (CDK5) don't home in on the appropriate location within the hippocampus. However, the loss of the homing signal doesn't keep the cells from integrating into the neural tissue around them, the researchers report in PLoS Biology. "A single gene seems to control orientation," Gage says. "We've separated the appropriate dendritic organization from the ability to make connections."
Previous research by the Gage group and other researchers had implied that CDK5 played a role in the integration of new neurons into the existing circuitry. In the most recent experiments, Gage and his colleagues used a retrovirus to both suppress CDK5 in the dividing neural progenitors in the hippocampus of adult mice and tag these cells with green fluorescent protein. Many of these CDK5-suppressed cells didn't integrate into the appropriate location in the molecular layer of the dentate gyrus. Instead they formed errant synapses with the cells that surround them. "[It] was really surprising that they form connections," says Sebastian Jessberger, lead author on the study, now at ETH in Zürich, Switzerland. "The brain doesn't realize that it's wrong. A year after those cells were born, they're still there."
Future studies will be needed to determine the exact molecular targets of CDK5 in these maturing neurons. However, roughly 50% of the CDK5-deficient cells do still make it to their target region and can recover normal function. Therefore, CDK5's role in neuronal targeting may be concentration dependent, or environmental factors in the correct niche may overcome a CDK5 deficiency, the researchers say. However, because the brain does not appear to correct for misplaced neurons, the work implies that careful placement of new neurons will be particularly important in neural regenerative therapies, Gage says.
CDK5 is a member of a family of molecules associated with cell-cycle regulation. "It's interesting that [CDK5] does not have an influence on proliferation but seems to have a role in sculpting dendritic formation," says Evan Snyder of the Burnham Institute in La Jolla, California. "That probably invites more scrutiny of this particular molecule and the role it's really playing."