Dendritic spine dysgenesis contributes to hyperreflexia after spinal cord injury

Abstract

Bandaru SP, Liu S, Waxman SG, Tan AM. Dendritic spine dysgenesis contributes to hyperreflexia after spinal cord injury. J Neurophysiol 113: 1598 -1615, 2015. First published December 10, 2014 doi:10.1152/jn.00566.2014.-Hyperreflexia and spasticity are chronic complications in spinal cord injury (SCI), with limited options for safe and effective treatment. A central mechanism in spasticity is hyperexcitability of the spinal stretch reflex, which presents symptomatically as a velocity-dependent increase in tonic stretch reflexes and exaggerated tendon jerks. In this study we tested the hypothesis that dendritic spine remodeling within motor reflex pathways in the spinal cord contributes to H-reflex dysfunction indicative of spasticity after contusion SCI. Six weeks after SCI in adult Sprague-Dawley rats, we observed changes in dendritic spine morphology on ␣-motor neurons below the level of injury, including increased density, altered spine shape, and redistribution along dendritic branches. These abnormal spine morphologies accompanied the loss of H-reflex ratedependent depression (RDD) and increased ratio of H-reflex to Mwave responses (H/M ratio). Above the level of injury, spine density decreased compared with below-injury spine profiles and spine distributions were similar to those for uninjured controls. As expected, there was no H-reflex hyperexcitability above the level of injury in forelimb H-reflex testing. Treatment with NSC23766, a Rac1-specific inhibitor, decreased the presence of abnormal dendritic spine profiles below the level of injury, restored RDD of the H-reflex, and decreased H/M ratios in SCI animals. These findings provide evidence for a novel mechanistic relationship between abnormal dendritic spine remodeling in the spinal cord motor system and reflex dysfunction in SCI.

Spinal cord motor neuron plasticity accompanies second‐degree burn injury and chronic pain

“…In our previous study of alpha‐motor neurons in the ventral horn, total, thin‐, and mushroom‐shaped dendritic spine densities increased following a contusion spinal cord injury (SCI) (Bandaru et al, ). Dendritic spines also redistributed spatially on dendritic branch locations closest to the cell body.…”

“…We identified and classified alpha‐motor neuron dendritic spines using profiling information from our previous publications (Bandaru et al, ; Zhao et al, ). Investigators blinded to treatment conditions performed all imaging studies and analyses.…”

“…In our previous work, we have identified a common structural motif of abnormal dendritic spine morphology strongly associated with hyperexcitability disorders, for example, pain and spasticity, following several traumatic injury events, including partial‐thickness burn injury (Bandaru, Liu, Waxman, & Tan, ; Guo et al, ; Tan et al, ; Wang et al, ; Zhao et al, ). However, despite circumstantial evidence demonstrating significant adverse effects in the spinal motor system after burn injury, no study has yet reported the presence of dendritic spine dysgenesis in these ventral horn motor neurons.…”

“…We performed a retrospective analysis of dendritic spine profiles in alpha‐motor neurons from adult mice with burn injury‐induced neuropathic pain. Mice with burn injury had a significant increase in dendritic spine density; in particular, mature mushroom‐shaped spines that have been associated with hyperexcitability in dorsal or ventral horn circuits (Bandaru et al, ; Tan, Choi, Waxman, & Hains, ). These postburn changes in dendritic spine morphology appeared to be Pak1‐signaling‐dependent, since treatment with romidepsin (an FDA‐approved Pak1‐inhibitor) restored dendritic spine profiles in motor neurons to levels similar to uninjured Sham animals.…”

Lumbar Myeloid Cell Trafficking into Locomotor Networks after Thoracic Spinal Cord Injury

“…Spinal shock results from structural and biochemical indices of maladaptive neuroplasticity regulated by neuroinflammation. Findings of aberrant spine formations throughout dorsal, intermediate, and ventral neuron networks support this mechanism (Bandaru et al, 2015; Hains and Waxman, 2006; Hansen et al, 2016; Tan et al, 2008). We postulate that remote inflammatory signaling jeopardizes the homeostatic balance of excitatory and inhibitory synaptic contacts in locomotor networks after SCI.…”