Selective Rab11 transport and the intrinsic regenerative ability of CNS axons
- University of Cambridge, United Kingdom
- University of Edinburgh, United Kingdom
- University of Leeds, United Kingdom
Abstract
Neurons lose intrinsic axon regenerative ability with maturation, but the mechanism remains unclear. Using an in-vitro laser axotomy model, we show a progressive decline in the ability of cut CNS axons to form a new growth cone and then elongate. Failure of regeneration was associated with increased retraction after axotomy. Transportation into axons becomes selective with maturation; we hypothesized that selective exclusion of molecules needed for growth may contribute to regeneration decline. With neuronal maturity Rab11 vesicles (which carry many molecules involved in axon growth) became selectively targeted to the somatodendritic compartment and excluded from axons. Their transport changed from bidirectional to retrograde. However, on overexpression Rab11 was mistrafficked into proximal axons, and these axons showed less retraction and enhanced regeneration after axotomy. These results suggest that the decline of intrinsic axon regenerative ability is associated with selective exclusion of key molecules, and that manipulation of transport can enhance regeneration.
Data availability
-
Maturation of cortical neuronsPublicly available at NCBI Gene Expression Omnibus (accession no: GSE92856).
Article and author information
Author details
Funding
Medical Research Council (G1000864)
- James Fawcett
Christopher and Dana Reeve Foundation (International Consortium)
- James Fawcett
European Research Council (ECMneuro)
- James Fawcett
GlaxoSmithKline International Scholarship
- Hiroaki Koseki
Honjo International Scholarship Foundation
- Hiroaki Koseki
Bristol Myers Squibb Graduate Studentship
- Hiroaki Koseki
National Institute of Health Research (Cambridge Biomedical Research Centre)
- James Fawcett
Czech ministry of education (CZ.02.1.01/0.0./0.0/15_003/0000419)
- Jessica CF Kwok
- James Fawcett
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Koseki et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,737
- views
-
- 640
- downloads
-
- 60
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Selective Rab11 transport and the intrinsic regenerative ability of CNS axons
eLife 6:e26956.
https://doi.org/10.7554/eLife.26956
Further reading
-
- Neuroscience
Although grid cells are one of the most well-studied functional classes of neurons in the mammalian brain, whether there is a single orientation and spacing value per grid module has not been carefully tested. We analyze a recent large-scale recording of medial entorhinal cortex to characterize the presence and degree of heterogeneity of grid properties within individual modules. We find evidence for small, but robust, variability and hypothesize that this property of the grid code could enhance the encoding of local spatial information. Performing analysis on synthetic populations of grid cells, where we have complete control over the amount heterogeneity in grid properties, we demonstrate that grid property variability of a similar magnitude to the analyzed data leads to significantly decreased decoding error. This holds even when restricted to activity from a single module. Our results highlight how the heterogeneity of the neural response properties may benefit coding and opens new directions for theoretical and experimental analysis of grid cells.
-
- Neuroscience
Childhood adversity is a strong predictor of developing psychopathological conditions. Multiple theories on the mechanisms underlying this association have been suggested which, however, differ in the operationalization of ‘exposure.’ Altered (threat) learning mechanisms represent central mechanisms by which environmental inputs shape emotional and cognitive processes and ultimately behavior. 1402 healthy participants underwent a fear conditioning paradigm (acquisition training, generalization), while acquiring skin conductance responses (SCRs) and ratings (arousal, valence, and contingency). Childhood adversity was operationalized as (1) dichotomization, and following (2) the specificity model, (3) the cumulative risk model, and (4) the dimensional model. Individuals exposed to childhood adversity showed blunted physiological reactivity in SCRs, but not ratings, and reduced CS+/CS- discrimination during both phases, mainly driven by attenuated CS+ responding. The latter was evident across different operationalizations of ‘exposure’ following the different theories. None of the theories tested showed clear explanatory superiority. Notably, a remarkably different pattern of increased responding to the CS- is reported in the literature for anxiety patients, suggesting that individuals exposed to childhood adversity may represent a specific sub-sample. We highlight that theories linking childhood adversity to (vulnerability to) psychopathology need refinement.
