PT  - JOURNAL ARTICLE
AU  - Tharkika Nagendran
AU  - Rebecca L. Bigler
AU  - Rylan Larsen
AU  - Benjamin D. Philpot
AU  - Anne Marion Taylor
TI  - Distal axotomy enhances retrograde presynaptic excitability onto injured pyramidal neurons via trans-synaptic signaling
AID  - 10.1101/065391
DP  - 2016 Jan 01
TA  - bioRxiv
PG  - 065391
4099  - http://biorxiv.org/content/early/2016/07/25/065391.short
4100  - http://biorxiv.org/content/early/2016/07/25/065391.full
AB  - Distal injury of long pyramidal tracts remodels cortical circuitry and leads to enhanced neuronal excitability, thus influencing recovery following injury. The neuron-specific contributions to this retrograde injury-induced hyper-excitability remain unclear due to the complex cellular composition and connectivity of the CNS. We developed a novel microfluidics-based in vitro model system to examine intrinsic synaptic remodeling following distal axotomy of long projection pyramidal neurons. We found that distal axotomy of rat pyramidal neurons caused dendritic spine loss at synapses onto the injured neurons followed by a delayed and persistent retrograde trans-synaptic enhancement in presynaptic excitability. Further, this hyper-excitability involved the specific elimination of inhibitory presynaptic terminals formed onto dendritic spines. We found that these changes required differential gene expression and axotomy decreased mRNA expression of the secreted factor netrin-1 coinciding with spine loss. Exogenous netrin-1 applied two days after injury normalized this presynaptic hyper-excitability and restored the fraction of inhibitory inputs onto injured neurons. These findings provide new insights of neuron-specific mechanisms that contribute to synaptic remodeling and demonstrate a novel model system for studying the response of pyramidal circuitry to axotomy.