Anne Marion Taylor’s lab publishes in Nature Communications on the cellular mechanisms of circuit remodeling following axon damage in the mammalian central nervous system.
Brain injury remodels circuitry within the brain to dramatically influence recovery outcomes. How this remodeling occurs, is largely unclear. The complexity of the mammalian central nervous system makes it challenging to study injury-induced circuit remodeling. Anne Marion Taylor’s lab developed a simplified cell-based models using microfluidic tools to study neuronal injury and its effect on remodeling. In their recently published paper in Nature Communications, they found that when axon damage occurs at pyramidal neurons—the neurons that are largely responsible for learning, memory, and cognition—a cascade of remodeling events is triggered, including loss of synapses and hyper-excitability at the surviving, intact end of the injured neuron. These events are consistent with in vivo injury models, suggesting that intrinsic signaling mechanisms within neurons mediate circuit remodeling. Their study also showed that inhibitory synapses are preferentially loss in the days following axon damage, likely contributing to neuronal hyper-excitability. Using their microfluidic approach, they investigated differences in gene expression in neurons cause by axon damage and identified netrin-1 as significantly reduced following injury. Netrin-1 is a secreted cue that is traditionally thought of in a developmental context, but also plays a role in synapse development and plasticity. By adding exogenous netrin-1 they were able to normalize the injury-induced changes in synapse loss, hyper-excitability and inhibition. These findings support netrin-1 signaling as a potential future therapeutic target for conditions involving injury-induced hyper-excitability, including following brain and spinal cord injury, stroke, and for epilepsy. Further their microfluidic model provides a useful new approach to study intrinsic mechanisms of neuron injury and circuit remodeling.
Nagendran, T. Larsen, R.S., Bigler, R.L., Frost, S.B., Philpot, B.D., Nudo, R.J. & Taylor, A.M.* Distal axotomy enhances retrograde presynaptic excitability onto injured pyramidal neurons via trans-synaptic signaling. Nature Communications 8(1):625, PMID: 28931811, 2017
** highlighted in Medical Press: https://medicalxpress.com/news/2017-09-brain-wiring.html