Abstract
Clinical spinal cord injury (SCI) is accompanied by comorbid peripheral injury in 47% of patients. Human and animal modeling data have shown that painful peripheral injuries undermine long-term recovery of locomotion through unknown mechanisms. Peripheral nociceptive stimuli induce maladaptive synaptic plasticity in dorsal horn sensory systems through AMPA receptor (AMPAR) phosphorylation and trafficking to synapses. Here we test whether ventral horn motor neurons in rats demonstrate similar experience-dependent maladaptive plasticity below a complete SCI in vivo. Quantitative biochemistry demonstrated that intermittent nociceptive stimulation (INS) rapidly and selectively increases AMPAR subunit GluA1 serine 831 phosphorylation and localization to synapses in the injured spinal cord, while reducing synaptic GluA2. These changes predict motor dysfunction in the absence of cell death signaling, suggesting an opportunity for therapeutic reversal. Automated confocal time-course analysis of lumbar ventral horn motor neurons confirmed a time-dependent increase in synaptic GluA1 with concurrent decrease in synaptic GluA2. Optical fractionation of neuronal plasma membranes revealed GluA2 removal from extrasynaptic sites on motor neurons early after INS followed by removal from synapses 2 h later. As GluA2-lacking AMPARs are canonical calcium-permeable AMPARs (CP-AMPARs), their stimulus- and time-dependent insertion provides a therapeutic target for limiting calcium-dependent dynamic maladaptive plasticity after SCI. Confirming this, a selective CP-AMPAR antagonist protected against INS-induced maladaptive spinal plasticity, restoring adaptive motor responses on a sensorimotor spinal training task. These findings highlight the critical involvement of AMPARs in experience-dependent spinal cord plasticity after injury and provide a pharmacologically targetable synaptic mechanism by which early postinjury experience shapes motor plasticity.
Highlights
In the human spinal cord injury (SCI) population there is a high incidence of concomitant peripheral injury, including lacerations, abrasions, and fractured limbs (Saboe et al, 1991; Sekhon and Fehlings, 2001; Wang et al, 2001; Hasler et al, 2011)
Serine 831 phosphorylation of synaptic GluA1 in the injured spinal cord Given that GluA2-lacking AMPA receptor (AMPAR) are calcium permeable (Hollmann et al, 1991), the current study provide a potential mechanism for prior findings that intermittent nociceptive stimulation (INS) engages calcium-dependent kinases, protein kinase C (PKC), and calcium-calmodulin-dependent kinase II (CaMKII; Baumbauer et al, 2007; Ferguson et al, 2008a; Huie et al, 2012a)
Our results demonstrate that peripheral nociceptive input below an acute complete SCI induces a form of AMPAmediated maladaptive synaptic plasticity that impairs future spinal cord training
Summary
Recent findings have demonstrated that painful stimuli below a spinal cord injury can affect future locomotor training and recovery in spinal cord injured patients (Bouffard et al, 2014), as well as in animal models (Ferguson et al, 2008a; Ferguson et al, 2012a; Ferguson et al, 2012b). The cellular and molecular mechanisms for this experience-dependent modulation of spinal cord plasticity are poorly understood. This work uncovers a novel synaptic mechanism by which peripheral nociceptive (painful) input following a spinal cord injury can undermine future adaptive spinal cord plasticity, providing a novel target for improving recovery after spinal cord injury, and mitigating aberrant forms of spinal neuroplasticity
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