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

Nature Communications, 2017 · DOI: 10.1038/s41467-017-00652-y · Published: August 7, 2017

Simple Explanation

Brain injuries can cause changes in the brain's wiring, even in areas far from the injury. However, we don't fully understand how this happens. This study used a special setup to injure nerve fibers (axons) far away from the main body of nerve cells (neurons). This allowed researchers to see how the injury affected the neurons and their connections (synapses). The researchers found that when an axon is cut, the neuron it belongs to loses some of its connections. However, the remaining connections become more active, and the neuron itself becomes more easily excitable. A protein called netrin-1 seems to be important for this process.

Study Duration

4 weeks to 18 weeks post-SCI

Participants

Adult male Fischer-344 inbred rats

Evidence Level

Level 2: Experimental study using in vitro and in vivo models

Key Findings

1
Axotomy causes retrograde dendritic spine loss at directly injured pyramidal neurons followed by retrograde presynaptic hyper-excitability.
2
Axotomy-induced hyper-excitability coincides with the elimination of inhibitory inputs onto injured neurons, including those formed onto dendritic spines.
3
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.

Research Summary

This study investigates how distal axon injury remodels synapses contacting injured neurons using a microfluidic approach to compartmentalize cultured neurons. The research demonstrates that axotomized pyramidal neurons undergo dendritic spine loss followed by a trans-synaptic enhancement in presynaptic excitability, coinciding with the loss of inhibitory inputs. The study identifies netrin-1 as significantly downregulated following axotomy, and exogenous application of netrin-1 restores spine density and normalizes presynaptic excitability, including inhibitory inputs.

Practical Implications

Therapeutic Potential

Netrin-1 signaling may be a therapeutic target for promoting recovery after CNS injuries.

Circuit Remodeling

Understanding the mechanisms of synaptic remodeling after axonal injury can inform strategies to promote adaptive plasticity.

Targeted Interventions

Interventions targeting specific signaling pathways can restore inhibitory balance and prevent hyper-excitability in injured neurons.

Study Limitations

1
In vitro model may not fully replicate the complexity of in vivo injury.
2
Study focuses on pyramidal neurons, and other cell types may respond differently.
3
Long-term effects of netrin-1 treatment were not examined.

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