Glutamate receptor plasticity and activity-regulated cytoskeletal associated protein regulation in the phrenic motor nucleus may mediate spontaneous recovery of the hemidiaphragm following chronic cervical spinal cord injury.
High cervical spinal cord hemisection results in paralysis of the ipsilateral hemidiaphragm; however, functional recovery of the paralyzed hemidiaphragm can occur spontaneously. The mechanisms mediating this recovery are unknown. In chronic, experimental contusive spinal cord injury, an upregulation of the NMDA receptor 2A subunit and a downregulation of the AMPA receptor GluR2 subunit have been correlated with improved hind limb motor recovery. Therefore, we hypothesized that NR2A is upregulated, whereas GluR2 is down-regulated following chronic C2 hemisection to initiate synaptic strengthening in respiratory motor pathways. Since NMDA receptor activation can lead to the delivery of AMPA receptor subunits to the post-synaptic membrane, we also hypothesized that there would be an upregulation of the GluR1 AMPA receptor subunit and that activity-regulated cytoskeletal associated protein may mediate the post-synaptic membrane delivery. Female rats were hemisected at C2 and allowed to recover for different time points following hemisection. At these time points, protein levels of NR2A, GluR1, and GluR2 subunits were assessed via Western blot analysis. Western blot analysis revealed that there were increases in NR2A subunit at six and twelve weeks post C2 hemisection. At six, twelve, and sixteen weeks post hemisection, the GluR1 subunit was increased over controls, whereas the GluR2 subunit decreased sixteen weeks post hemisection. Immunocytochemical data qualitatively supported these findings. Results also indicated that activity-regulated cytoskeletal associated protein may be associated with the above changes. These findings suggest a role of NR2A, GluR1, and GluR2 in mediating chronic spontaneous functional recovery of the paralyzed hemidiaphragm following cervical spinal cord hemisection.
Cellular and Clinical Neurobiology Program, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201, USA.
Warren J
WJ
Alilain
Harry G
HG
Goshgarian
D000704:Analysis of Variance; D000818:Animals; D002574:Cervical Vertebrae; D002908:Chronic Disease; D003964:Diaphragm / Q000503:physiopathology*; D004195:Disease Models, Animal; D004576:Electromyography; D005260:Female; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000502:physiology*; D009046:Motor Neurons; D009473:Neuronal Plasticity / Q000502:physiology*; D010791:Phrenic Nerve / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000473:pathology* / Q000503:physiopathology; D013997:Time Factors; D018998:Wheat Germ Agglutinin-Horseradish Peroxidase Conjugate / Q000378:metabolism
C120997:NR2A NMDA receptor; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D018998:Wheat Germ Agglutinin-Horseradish Peroxidase Conjugate; C104722:glutamate receptor ionotropic, AMPA 2