Cellular Pruning Shears Reshape Connections in Adults

The cortex is a remarkably adaptable structure. Deprive a small region of input, and axons from neighboring areas undergo exuberant outgrowth and pruning, in order to reactivate the freed-up real estate. While scientists know what causes new axons to sprout, they have yet to work out how axons get trimmed in adults. Now, scientists led by Charles Gilbert, Rockefeller University, New York, reporting in the September 18 Journal of Neuroscience, implicate the protein death receptor 6 (DR6) in the pruning of axons in adult mice. A previous study had tied DR6 to the amyloid precursor protein (APP) in neurodevelopment. "This new study brings [the DR6 finding] to an adult plasticity-related phenomenon, which brings it a step closer to relevance in Alzheimer's disease," said Dale Bredesen, Buck Institute, Novato, California, who was not involved in the project.

Co-author Marc Tessier-Lavigne and colleagues previously reported that DR6, an orphan member of the tumor necrosis factor receptor superfamily, helps prune axons during development, when the nervous system is clearing away unused neuronal connections (see ARF related news story). In the same study, the researchers reported that APP interacts with the DR6 receptor, sets off an apoptotic cascade, and leads to axonal pruning and neurodegeneration in embryonic neurons. The involvement of APP hinted that DR6 might contribute to axonal trimming and cell death in AD, however, it was unclear whether the DR6 pathway also functioned in pruning processes of the adult brain.

To test that possibility, first author Sally Marik and colleagues studied DR6 knockout mice. They compared how the DR6-deficient cortex responded vis-a-vis that of wild-type cortex when the scientists removed selected whiskers, each of which connects to a defined somatosensory field in the brain. For a view of the brain in live mice, the researchers anesthetized each mouse and removed a small piece of skull over the area of the cortex that receives input from the whiskers. They then labeled excitatory neurons with a red fluorescent protein and inhibitory ones with a green one and patched up the opening with a glass cover. That left a window through which the researchers could follow axonal changes with 2-photon microscopy.

Before plucking whiskers, the researchers imaged the axons and found them to be relatively stable in both wild-type and DR6 knockout mice, with no appreciable pruning or sprouting in either group. However, things looked quite different once two rows of whiskers were removed. In wild-type mice, excitatory axons from the plucked whiskers shrank away within a day, while axons coming from adjacent rows of whiskers grew in. Inhibitory neurons also underwent extensive trimming and growth. DR6 knockout mice, on the other hand, showed almost no pruning in excitatory neurons. Some inhibitory neurons did get a trim, though to a much smaller extent than in wild-type mice. This suggests that pathways other than DR6 contribute to the pruning of inhibitory neurons.

"The authors have presented a convincing case that DR6 plays an important role in axonal pruning and cortical plasticity," wrote Hui Zheng, Baylor College of Medicine, Houston, Texas, to Alzforum in an email. Zheng was not involved with the project. However, she points out that the authors propose no mechanism. While the Rockefeller scientists work on that aspect, they will also investigate whether perceptual learning is associated with a similar kind of axonal modification. "We think that lesions may invoke the same mechanisms that are used in normal processes of experience-dependent change," Gilbert said.

What implications, if any, do these findings have for neurodegenerative disease? "The observation that DR6 functions in pruning processes of the adult brain, together with the fact that it interacts with APP, increases our interest in determining whether DR6 contributes to AD or other neurodegenerative diseases," said Tessier-Lavigne. He pointed out supporting evidence from a recent study suggesting that a DR6-containing complex with the p75 neurotrophin receptor mediates the toxic effects of Aβ on cultured cortical neurons (see Hu et al., 2013). However, it remains unclear whether DR6 is hyperactivated in Alzheimer's. "That's one of the big questions—is this a mechanism at work in Alzheimer's or is it a coincidence that [DR6] can be activated by a fragment of APP?" said Bredesen.

Gilbert speculated that some of the symptoms associated with AD could be accounted for by abnormalities in axonal pruning. "Although cell death may be an endpoint, some of the functional loss may not be due to cell death but to changes in the ability to undergo axonal plasticity," he told Alzforum. He and colleagues will present new data on what knocking out APP does to axonal pruning in these mice at the Society for Neuroscience annual meeting in San Diego in November. "This may provide a new avenue for thinking about the role of APP in normal processing," Gilbert told Alzforum.—Gwyneth Dickey Zakaib

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References

News Citations

  1. Keystone: Death Receptor Ligand—New Role for APP, New Model for AD? PAPER RETRACTED.

Paper Citations

  1. Hu Y, Lee X, Shao Z, Apicco D, Huang G, Gong BJ, Pepinsky RB, Mi S. A DR6/p75(NTR) complex is responsible for β-amyloid-induced cortical neuron death. Cell Death Dis. 2013;4:e579. PubMed.

Further Reading

Papers

  1. Zhang C, Browne A, Kim DY, Tanzi RE. Familial Alzheimer's disease mutations in presenilin 1 do not alter levels of the secreted amyloid-beta protein precursor generated by beta-secretase cleavage. Curr Alzheimer Res. 2010 Feb;7(1):21-6. PubMed.
  2. Guo Q, Li H, Gaddam SS, Justice NJ, Robertson CS, Zheng H. Amyloid precursor protein revisited: neuron-specific expression and highly stable nature of soluble derivatives. J Biol Chem. 2012 Jan 20;287(4):2437-45. PubMed.
  3. Hu Y, Lee X, Shao Z, Apicco D, Huang G, Gong BJ, Pepinsky RB, Mi S. A DR6/p75(NTR) complex is responsible for β-amyloid-induced cortical neuron death. Cell Death Dis. 2013;4:e579. PubMed.
  4. Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009 Feb 19;457(7232):981-9. PubMed. RETRACTED

Primary Papers

  1. Marik SA, Olsen O, Tessier-Lavigne M, Gilbert CD. Death receptor 6 regulates adult experience-dependent cortical plasticity. J Neurosci. 2013 Sep 18;33(38):14998-5003. PubMed.

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