title: Permanent central synaptic disconnection of proprioceptors after nerve injury and regeneration. I. Loss of VGLUT1/IA synapses on motoneurons.
abstract: Motor and sensory proprioceptive axons reinnervate muscles after peripheral nerve transections followed by microsurgical reattachment; nevertheless, motor coordination remains abnormal and stretch reflexes absent. We analyzed the possibility that permanent losses of central IA afferent synapses, as a consequence of peripheral nerve injury, are responsible for this deficit. VGLUT1 was used as a marker of proprioceptive synapses on rat motoneurons. After nerve injuries synapses are stripped from motoneurons, but while other excitatory and inhibitory inputs eventually recover, VGLUT1 synapses are permanently lost on the cell body (75-95% synaptic losses) and on the proximal 100 μm of dendrite (50% loss). Lost VGLUT1 synapses did not recover, even many months after muscle reinnervation. Interestingly, VGLUT1 density in more distal dendrites did not change. To investigate whether losses are due to VGLUT1 downregulation in injured IA afferents or to complete synaptic disassembly and regression of IA ventral projections, we studied the central trajectories and synaptic varicosities of axon collaterals from control and regenerated afferents with IA-like responses to stretch that were intracellularly filled with neurobiotin. VGLUT1 was present in all synaptic varicosities, identified with the synaptic marker SV2, of control and regenerated afferents. However, regenerated afferents lacked axon collaterals and synapses in lamina IX. In conjunction with the companion electrophysiological study [Bullinger KL, Nardelli P, Pinter MJ, Alvarez FJ, Cope TC. J Neurophysiol (August 10, 2011). doi:10.1152/jn.01097.2010], we conclude that peripheral nerve injuries cause a permanent retraction of IA afferent synaptic varicosities from lamina IX and disconnection with motoneurons that is not recovered after peripheral regeneration and reinnervation of muscle by sensory and motor axons.
authors.affiliation: Department of Neuroscience, Cell Biology, and Physiology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, USA. francisco.j.alvarez@emory.edu
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Alvarez
authors.forename: Haley E
authors.initials: HE
authors.lastname: Titus-Mitchell
authors.forename: Katie L
authors.initials: KL
authors.lastname: Bullinger
authors.forename: Michal
authors.initials: M
authors.lastname: Kraszpulski
authors.forename: Paul
authors.initials: P
authors.lastname: Nardelli
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Cope
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000502:physiology; D019771:Axotomy; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D004576:Electromyography; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D009046:Motor Neurons / Q000473:pathology / Q000502:physiology*; D018482:Muscle, Skeletal / Q000294:innervation; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology; D009416:Nerve Regeneration / Q000502:physiology*; D009475:Neurons, Afferent / Q000502:physiology; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000473:pathology; D011434:Proprioception / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000502:physiology; D012026:Reflex, Stretch / Q000502:physiology; D013979:Tibial Nerve / Q000293:injuries / Q000473:pathology / Q000503:physiopathology*; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism*; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism / Q000502:physiology
chemical_list: C493475:Slc17a6 protein, rat; C493466:Slc17a7 protein, rat; D050598:Vesicular Glutamate Transport Protein 1; D050599:Vesicular Glutamate Transport Protein 2; C070614:neurobiotin; D001710:Biotin