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 2016
UL http://biorxiv.org/content/early/2016/10/19/065391.abstract
AB Injury of descending motor tracts remodels cortical circuitry and leads to enhanced neuronal excitability, thus influencing recovery following injury. The neuron-specific contributions remain unclear due to the complex cellular composition and connectivity of the CNS. We developed a microfluidics-based in vitro model system to examine intrinsic synaptic remodeling following axon damage. We found that distal axotomy of cultured rat pyramidal neurons caused dendritic spine loss at synapses onto the injured neurons followed by a persistent retrograde enhancement in presynaptic excitability over days. These in vitro results mirrored hyper-activity of directly injured corticospinal neurons in hindlimb motor cortex layer Vb following spinal cord contusion. In vitro axotomy-induced hyper-excitability coincided with elimination of inhibitory presynaptic terminals, including those formed onto dendritic spines. We identified netrin-1 as downregulated following axotomy and exogenous netrin-1 applied 2 days after injury normalized spine density, presynaptic excitability, and the fraction of inhibitory inputs onto injured neurons. These findings demonstrate a novel model system for studying the response of pyramidal circuitry to axotomy and provide new insights of neuron-specific mechanisms that contribute to synaptic remodeling.