IP3R-mediated intra-axonal Ca2+ release contributes to secondary axonal degeneration following contusive spinal cord injury

Secondary axonal loss contributes to the persistent functional disability following trauma. Consequently, preserving axons following spinal cord injury (SCI) is a major therapeutic goal to improve neurological outcome; however, the complex molecular mechanisms that mediate secondary axonal degeneration remain unclear. We previously showed that IP3R-mediated Ca2+ release contributes to axonal dieback and axonal loss following an ex vivo laser-induced SCI. Nevertheless, targeting IP3R in a clinically relevant in vivo model of SCI and determining its contribution to secondary axonal degeneration has yet to be explored. Here we used intravital two-photon excitation microscopy to assess the role of IP3R in secondary axonal degeneration in real-time after a contusive-SCI in vivo. To visualize Ca2+ changes specifically in spinal axons over time, adult 6–8 week-old triple transgenic Avil-Cre:Ai9:Ai95 (sensory neuron-specific expression of tdTomato and the genetic calcium indicator GCaMP6f) mice were subjected to a mild (30 kdyn) T12 contusive-SCI and received delayed treatment with the IP3R blocker 2-APB (100 μM, intrathecal delivery at 3, and 24 h following injury) or vehicle control. To determine the IP3R subtype involved, we knocked-down IP3R3 using capped phosphodiester oligonucleotides. Delayed treatment with 2-APB significantly reduced axonal spheroids, increased axonal survival, and reduced intra-axonal Ca2+ accumulation within dorsal column axons at 24 h following SCI in vivo. Additionally, knockdown of IP3R3 yielded increased axon survival 24 h post-SCI. These results suggest that IP3R-mediated Ca2+ release contributes to secondary axonal degeneration in vivo following SCI.

Abstract licence: CC BY-NC

1. 7.

   Generation and Characterization of an Advillin -Cre Driver Mouse Line · 2011

39 more references, whose wording the paper’s licence keeps private.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.