title: AMPA Receptor Phosphorylation and Synaptic Colocalization on Motor Neurons Drive Maladaptive Plasticity below Complete Spinal Cord Injury.
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.
authors.affiliation: Department of Neurological Surgery, Brain and Spinal Injury Center, University of California San Francisco , San Francisco, California 94110.
authors.forename: J Russell
authors.identifier: 0000-0001-5594-4277
authors.initials: JR
authors.lastname: Huie
authors.affiliation: Department of Neurological Surgery, Brain and Spinal Injury Center, University of California San Francisco , San Francisco, California 94110.
authors.forename: Ellen D
authors.initials: ED
authors.lastname: Stuck
authors.affiliation: Department of Neurobiology, University of Pittsburgh , Pittsburgh, Pennsylvania 15261.
authors.forename: Kuan H
authors.identifier: 0000-0001-9000-3317
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Department of Neurological Surgery, Brain and Spinal Injury Center, University of California San Francisco , San Francisco, California 94110 ; San Francisco Veterans Affairs Medical Center , San Francisco, California 94121.
authors.forename: Karen-Amanda
authors.initials: KA
authors.lastname: Irvine
authors.affiliation: Department of Neurological Surgery, Brain and Spinal Injury Center, University of California San Francisco , San Francisco, California 94110.
authors.forename: Michael S
authors.identifier: 0000-0001-9463-3631
authors.initials: MS
authors.lastname: Beattie
authors.affiliation: Department of Neurological Surgery, Brain and Spinal Injury Center, University of California San Francisco , San Francisco, California 94110.
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Bresnahan
authors.affiliation: Department of Psychology, Texas A&M University , College Station, Texas 77841.
authors.forename: James W
authors.identifier: 0000-0002-6191-0433
authors.initials: JW
authors.lastname: Grau
authors.affiliation: Department of Neurological Surgery, Brain and Spinal Injury Center, University of California San Francisco , San Francisco, California 94110 ; San Francisco Veterans Affairs Medical Center , San Francisco, California 94121.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Ferguson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000502:physiology; D004195:Disease Models, Animal; D006614:Hindlimb / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D018613:Microscopy, Confocal; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D059225:Nociception / Q000502:physiology; D010766:Phosphorylation; D021381:Protein Transport; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000473:pathology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D018091:Receptors, AMPA
keywords: AMPA receptor; motor neuron; nociception; plasticity; spinal cord injury; spinal learning