RT Journal Article
SR Electronic
T1 Distal axotomy enhances retrograde presynaptic excitability onto injured pyramidal neurons via trans-synaptic signaling
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 065391
DO 10.1101/065391
A1 Tharkika Nagendran
A1 Rylan S. Larsen
A1 Rebecca L. Bigler
A1 Shawn B. Frost
A1 Benjamin D. Philpot
A1 Randolph J. Nudo
A1 Anne Marion Taylor
YR 2017
UL http://biorxiv.org/content/early/2017/06/01/065391.abstract
AB 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.