Unique Axon-to-Soma Signaling Pathways Mediate Dendritic Spine Loss and Hyper-Excitability Post-axotomy.

Tharkika Nagendran,Anne Marion Taylor

doi:10.3389/fncel.2019.00431

Abstract

Axon damage may cause axon regeneration, retrograde synapse loss, and hyper-excitability, all of which affect recovery following acquired brain injury. While axon regeneration is studied extensively, less is known about signaling mediating retrograde synapse loss and hyper-excitability, especially in long projection pyramidal neurons. To investigate intrinsic injury signaling within neurons, we used an in vitro microfluidic platform that models dendritic spine loss and delayed hyper-excitability following remote axon injury. Our data show that sodium influx and reversal of sodium calcium exchangers (NCXs) at the site of axotomy, mediate dendritic spine loss following axotomy. In contrast, sodium influx and NCX reversal alone are insufficient to cause retrograde hyper-excitability. We found that calcium release from axonal ER is critical for the induction of hyper-excitability and inhibition loss. These data suggest that synapse loss and hyper-excitability are uncoupled responses following axon injury. Further, axonal ER may play a critical and underappreciated role in mediating retrograde hyper-excitability within the CNS.

Highlights

Acute neural injuries cause profound axon damage
We previously found that blocking local activity at the site of injury using this method prevented dendritic spine loss 24 h post-axotomy (Nagendran et al, 2017), suggesting calcium and sodium influx at the site of injury are key mediators of this neuronal injury response
Hyper-excitability following acquired brain injury leads to longterm effects, such as persistent seizures, chronic pain, and spasticity

Summary

Introduction

Acute neural injuries (e.g., stroke, traumatic brain injury, and spinal cord injury) cause profound axon damage. Axon damage triggers an intra-cellular signaling cascade to effect neuronal injury responses, including axon regeneration, retrograde synapse loss, and hyper-excitability. These downstream responses are critical for recovery following injury. The intrinsic neuronal signaling mechanisms mediating retrograde synapse loss and hyper-excitability, in particular, remain poorly understood. Breach of the axonal membrane following axon injury causes an influx of ions, including calcium and sodium, into the intra-axonal space. The increase in sodium ions through voltage-gated sodium channels causes reversal of sodium-calcium exchangers (NCXs) located on the plasma membrane, mitochondria and ER, enhancing local intra-axonal calcium levels (Persson et al, 2013).

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Results

Conclusion