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Nat Commun. 2017 Sep 20;8(1):625. doi: 10.1038/s41467-017-00652-y.

Distal axotomy enhances retrograde presynaptic excitability onto injured pyramidal neurons via trans-synaptic signaling.

Author information

1
UNC/NCSU Joint Department of Biomedical Engineering, UNC-Chapel Hill, Campus box 7575, Chapel Hill, NC, 27599-7575, USA.
2
UNC Neuroscience Center, UNC-Chapel Hill, Campus box 7250, Chapel Hill, NC, 27599-7250, USA.
3
Department of Cell Biology and Physiology, UNC-Chapel Hill, Campus box 7545, Chapel Hill, NC, 27599-7545, USA.
4
Allen Institute for Brain Science, 615 Westlake Avenue North, Seattle, WA, 98109, USA.
5
Curriculum in Genetics and Molecular Biology, UNC-Chapel Hill, Chapel Hill, NC, 27599, USA.
6
Landon Center On Aging, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA.
7
Department of Rehabilitation Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA.
8
Carolina Institute for Developmental Disabilities, Campus box 7255, Chapel Hill, NC, 27599-7255, USA.
9
UNC/NCSU Joint Department of Biomedical Engineering, UNC-Chapel Hill, Campus box 7575, Chapel Hill, NC, 27599-7575, USA. anne.marion.taylor@gmail.com.
10
UNC Neuroscience Center, UNC-Chapel Hill, Campus box 7250, Chapel Hill, NC, 27599-7250, USA. anne.marion.taylor@gmail.com.
11
Carolina Institute for Developmental Disabilities, Campus box 7255, Chapel Hill, NC, 27599-7255, USA. anne.marion.taylor@gmail.com.

Abstract

Injury of CNS nerve tracts remodels circuitry through dendritic spine loss and hyper-excitability, thus influencing recovery. Due to the complexity of the CNS, a mechanistic understanding of injury-induced synaptic remodeling remains unclear. Using microfluidic chambers to separate and injure distal axons, we show that axotomy causes retrograde dendritic spine loss at directly injured pyramidal neurons followed by retrograde presynaptic hyper-excitability. These remodeling events require activity at the site of injury, axon-to-soma signaling, and transcription. Similarly, directly injured corticospinal neurons in vivo also exhibit a specific increase in spiking following axon injury. Axotomy-induced hyper-excitability of cultured neurons coincides with elimination of inhibitory inputs onto injured neurons, including those formed onto dendritic spines. Netrin-1 downregulation occurs following axon injury and exogenous netrin-1 applied after injury normalizes spine density, presynaptic excitability, and inhibitory inputs at injured neurons. Our findings show that intrinsic signaling within damaged neurons regulates synaptic remodeling and involves netrin-1 signaling.Spinal cord injury can induce synaptic reorganization and remodeling in the brain. Here the authors study how severed distal axons signal back to the cell body to induce hyperexcitability, loss of inhibition and enhanced presynaptic release through netrin-1.

PMID:
28931811
PMCID:
PMC5607003
DOI:
10.1038/s41467-017-00652-y
[Indexed for MEDLINE]
Free PMC Article

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