Newborn Neurons in the Adult Brain Can Settle in the Wrong Neighbourhood

Newborn Neurons in the Adult Brain Can Settle in the Wrong Neighbourhood Wednesday, 12 November 2008 A new study published in this week's PLoS Biology could have significant consequences for neural tissue transplantation to treat brain injuries or neural degeneration. Researchers at the Salk Institute for Biological Studies report that inactivating a specific gene in adult neural stem cells makes nerve cells emerging from those precursors form connections in the wrong part of the adult brain. The research team, led by Professor Fred H. Gage, Ph.D., discovered that a protein called cdk5 is necessary for both correct elaboration of highly branched and complex dendrites, a kind of antennae, which are extended by neurons. Cdk5 is also involved in the proper migration of cells bearing those antennae. Previously described functions of cdk5 are manifold, among them neuronal migration and dendritic path-finding of neurons born during embryonic development. "The surprising element was that the dendrites of newborn granule cells in the adult hippocampus lacking cdk5 stretched in the wrong direction and actually formed synapses with the wrong cells," explains Gage. Synapses are the specialized contact points where dendrites receive input from the long processes, or axons, of neighbouring neurons. The investigators injected retroviruses into the hippocampus of adult mice to tag and knock out cdk5 activity in newborn granule cell neurons. These findings offer extremely valuable, unanticipated insight. "Our data shows that cells that fail to find their 'right spot' might actually become integrated into the brain and possibly interfere with normal information processing," says the study's lead author Sebastian Jessberger, M.D., a former postdoc in the Gage lab and now an assistant professor at the Swiss Federal Institute of Technology in Zurich, Switzerland. "We found that dendrites of cells lacking cdk5 seemed to integrate into the brain no matter what direction they grew in," he says. Gage notes that the findings "reflect the need for therapeutic approaches that will assure that cells used in regenerative medicine are strategically placed so that they will make appropriate rather than promiscuous connections."

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Newborn neurons deficient in cdk5 (green) extend aberrant dendrites that nonetheless synaptically integrate into the pre-existing dentate circuitry containing neurons (red) and glial cells (blue). From: For New Neurons in an Old Brain, cdk5 Shows the Way Robinson R PLoS Biology Vol. 6, No. 11, e291 doi:10.1371/journal.pbio.0060291.

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In fact, the inappropriate synaptic connections made by cdk5-deficient cells persisted for months after the treatment with cdk5-antagonizing retroviruses. "One might have predicted that aberrant maturing nerve cells would get kicked out of the circuitry later on," reports Jessberger, who followed the behaviour of newborn granule cells in treated mice long after cdk5 activity was eliminated. "Even after one year, some of those cells remained in the wrong part of the hippocampus." "The nice part of this story is that it emerged from a systems genetics approach we used in a previous study," says Gage. "It continues our effort to apply genetic analysis to find chromosomal regions harbouring genes that may play a critical role in neurogenesis." Reference: Cdk5 regulates accurate maturation of newborn granule cells in the adult hippocampus Sebastian Jessberger, Stefan Aigner, Gregory D. Clemenson Jr., Nicolas Toni, D. Chichung Lie, Özlem Karalay, Rupert Overall, Gerd Kempermann, Fred H. Gage PLoS Biol (2008) 6(11): e272. doi:10.1371/journal.pbio.0060272 See also: For New Neurons in an Old Brain, cdk5 Shows the Way Richard Robinson PLoS Biol (2008), 6(11): e291 doi:10.1371/journal.pbio.0060291 ......... ZenMaster

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For more on stem cells and cloning, go to CellNEWS at http://cellnews-blog.blogspot.com/ and http://www.geocities.com/giantfideli/index.html

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