The impact of training and neurotrophins on functional recovery after complete spinal cord transection: cellular and molecular mechanisms contributing to motor improvement

• Autorzy: Skup M. , Ziemlinska E. , Gajewska-Wozniak O. , Platek R. , Maciejewska A. , Czarkowska-Bauch J.
• Języki publikacji: EN

Abstrakty

EN

Beneficial effects of locomotor training on the functional recovery after complete transection of the spinal cord indicate that in chronic spinal animals spontaneous recovery processes are enhanced and shaped by the training. The mechanisms of that use-dependent improvement are still not fully understood. This review tackles three aspects of this issue: (1) neurochemical attributes of functional improvement showing that concentrations of excitatory and inhibitory amino acids in the lumbar spinal segments, which were changed after transection, normalize after the training, or even raise beyond normal. As it does not translate to functional equilibrium between excitatory and inhibitory neurotransmission and may lead to hyperexcitability, the postsynaptic mechanisms which might be responsible for the hyperexcitability are discussed, including (i) dysfunction of K+-Cl- cotransporter KCC2, which controls the strength and robustness of inhibition, and (ii) altered function of 5-HT2 receptors, which may be targeted to restore KCC2 activity and intrinsic inhibition; (2) morphological changes of lumbar motoneurons and their inputs related to functional improvement of spinal animals, pointing to use-dependent diminution/ reversal of the atrophy of the dendritic tree of the hindlimb motoneurons and of their synaptic impoverishment, which in paraplegic animals differs depending on the degree of disuse of the muscles; (3) the role of neurotrophins in motor improvement of spinal animals showing, that increases in neurotrophins due to training or due to efficient viral vector-based transgene expression, that might be responsible for the enrichment of the dendritic tree, elongation of processes and influence neurotransmitter systems in the areas subjected to plastic modifications after injury, correlate with improvement of locomotor functions.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2014
• Tom: 74
• Numer: 2
• Opis fizyczny: p.121-141,fig,ref.

Twórcy

autor

Skup M.

• Laboratory of Reinnervation Processes, Department of Neurophysiology, Nencki Institute of Experimental Biology PAS, Warsaw, Poland

autor

Ziemlinska E.

• Laboratory of Reinnervation Processes, Department of Neurophysiology, Nencki Institute of Experimental Biology PAS, Warsaw, Poland

autor

Gajewska-Wozniak O.

• Laboratory of Reinnervation Processes, Department of Neurophysiology, Nencki Institute of Experimental Biology PAS, Warsaw, Poland

autor

Platek R.

• Laboratory of Reinnervation Processes, Department of Neurophysiology, Nencki Institute of Experimental Biology PAS, Warsaw, Poland

autor

Maciejewska A.

• Laboratory of Reinnervation Processes, Department of Neurophysiology, Nencki Institute of Experimental Biology PAS, Warsaw, Poland

autor

Czarkowska-Bauch J.

• Laboratory of Reinnervation Processes, Department of Neurophysiology, Nencki Institute of Experimental Biology PAS, Warsaw, Poland

Bibliografia

• Aid T, Kazantseva A, Piirsoo M, Palm K, Timmusk T (2007) Mouse and rat BDNF gene structure and expression revisited. J Neurosci Res 85: 525-535.
• Alaimo MA, Smith JL, Roy RR, Edgerton VR (1984) EMG activity of slow and fast ankle extensors following spinal cord transection. J Appl Physiol Respir Environ Exerc Physiol 56: 1608-1613.
• Bakhit C, Armanini M, Wong WL, Bennett GL, Wrathall JR (1991) Increase in nerve growth factor-like immunoreac- tivity and decrease in choline acetyltransferase following contusive spinal cord injury. Brain Res 554: 264-271.
• Barbeau H, Fung J (2001) The role of rehabilitation in the recovery of walking in the neurological population. Curr Opin Neurol 14: 735-740.
• Barbeau H, Rossignol S (1987) Recovery of locomotion after chronic spinalization in the adult cat. Brain Res 412: 84-95.
• Barbeau H, Ladouceur M, Norman KE, Pépin A, Leroux A (1999a) Walking after spinal cord injury: evaluation, treatment, and functional recovery. Arch Phys Med Rehabil 80: 225-235.
• Barbeau H, McCrea DA, O'Donovan MJ, Rossignol S, Grill WM, Lemay MA (1999b) Tapping into spinal circuits to restore motor function. Brain Res Brain Res Rev 30: 27-51.
• Beattie MS, Harrington AW, Lee R, Kim JY, Boyce SL, Longo FM, Bresnahan JC, Hempstead BL, Yoon SO (2002) ProNGF induces p75-mediated death of oligoden¬drocytes following spinal cord injury. Neuron 36: 375¬386.
• Bos R, Sadlaoud K, Boulenguez P, Buttigieg D, Liabeuf S, Brocard C, Haase G, Bras H, Vinay L (2013) Activation of 5-HT2A receptors upregulates the function of the neu¬ronal K-Cl cotransporter KCC2. Proc Natl Acad Sci U S A 110: 348-353.
• Boulenguez P, Liabeuf S, Bos R, Bras H, Jean-Xavier C, Brocard C, Stil A, Darbon P, Cattaert D, Delpire E, Marsala M, Vinay L (2010) Down-regulation of the potassium-chloride cotransporter KCC2 contributes to spasticity after spinal cord injury. Nat Med 16: 302-307.
• Boyce VS, Park J, Gage FH, Mendell LM (2012) Differential effects of brain-derived neurotrophic factor and neurotro- phin-3 on hindlimb function in paraplegic rats. Eur J Neurosci 35: 221-232.
• Bramham CR, Messaoudi E (2005) BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 76: 99-125.
• Brown A, Ricci MJ, Weaver LC (2004) NGF message and protein distribution in the injured rat spinal cord. Exp Neurol 188: 115-127.
• Button DC, Kalmar JM, Gardiner K, Marqueste T, Zhong H, Roy RR, Edgerton VR, Gardiner PF (2008) Does elimina¬tion of afferent input modify the changes in rat motoneu- rone properties that occur following chronic spinal cord transection? J Physiol 586: 529-544.
• Calancie B, Needham-Shropshire B, Jacobs P, Willer K, Zych G, Green BA (1994) Involuntary stepping after chronic spinal cord injury. Evidence for a central rhythm generator for locomotion in man. Brain 117: 1143-1159.
• Calancie B, Molano MR, Broton JG (2002) Interlimb reflex¬es and synaptic plasticity become evident months after human spinal cord injury. Brain 125: 1150-1161.
• Cantoria MJ, See PA, Singh H, de Leon RD (2011) Adaptations in glutamate and glycine content within the lumbar spinal cord are associated with the generation of novel gait patterns in rats following neonatal spinal cord transection. J Neurosci 31: 18598-18605.
• Cao XH, Chen SR, Li L, Pan HL (2012) Nerve injury increases brain-derived neurotrophic factor levels to sup¬press BK channel activity in primary sensory neurons. J Neurochem 121: 944-953.
• Chao HT, Zoghbi HY (2009) The yin and yang of MeCP2 phosphorylation. Proc Natl Acad Sci U S A 106: 4577¬4578.
• Chen WG, Chang Q, Lin Y, Meissner A, West AE, Griffith EC, Jaenisch R, Greenberg ME (2003) Derepression of BDNF transcription involves calcium-dependent phos¬phorylation of MeCP2. Science 302: 885-889.
• Cho HC, Kim J, Kim S, Son YH, Lee N, Jung SH (2012) The concentrations of serum, plasma and platelet BDNF are all increased by treadmill VODmax performance in healthy college men. Neurosci Lett 519: 78-83.
• Cohen-Cory S (2002) The developing synapse: construction and modulation of synaptic structures and circuits. Science 298: 770-776.
• Copray S, Kernell D (2000) Neurotrophins and trk-receptors in adult rat spinal motoneurons: differences related to cell size but not to 'slow/fast' specialization. Neurosci Lett 289: 217-220.
• Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438: 1017-1021.
• D'Amico JM, Murray KC, Li Y, Chan KM, Finlay MG, Bennett DJ, Gorassini MA (2013) Constitutively active 5-HT2/alpha1 receptors facilitate muscle spasms after human spinal cord injury. J Neurophysiol 109: 1473-1484.
• D'Amico JM, Condliffe EG, Martins KJ, Bennett DJ, Gorassini MA (2014) Recovery of neuronal and network excitability after spinal cord injury and implications for spasticity. Front Integr Neurosci 8: 36.
• Dai Y, Jordan LM (2010) Multiple patterns and components of persistent inward current with serotonergic modulation in locomotor activity-related neurons in Cfos-EGFP mice. J Neurophysiol 103: 1712-1727.
• de Leon RD, See PA, Chow CH (2011) Differential effects of low versus high amounts of weight supported treadmill training in spinally transected rats. J Neurotrauma 28: 1021-1033.
• Deardorff AS, Romer SH, Deng Z, Bullinger KL, Nardelli P, Cope TC, Fyffe RE (2013) Expression of postsynaptic Ca2+-activated K+ (SK) channels at C-bouton synapses in mammalian lumbar -motoneurons. J Physiol 591: 875-897.
• Demediuk P, Daly MP, Faden AI (1989) Effect of impact trauma on neurotransmitter and nonneurotransmitter amino acids in rat spinal cord. J Neurochem 52: 1529¬1536.
• Diaz-Ruiz A, Salgado-Ceballos H, Montes S, Maldonado V, Tristan L, Alcaraz-Zubeldia M, Rios C (2007) Acute alterations of glutamate, glutamine, GABA, and other amino acids after spinal cord contusion in rats. Neurochem Res 32: 57-63.
• Dietz V, Colombo G, Jensen L, Baumgartner L (1995) Locomotor capacity of spinal cord in paraplegic patients. Ann Neurol 37: 574-582.
• Dietz V, Wirz M, Curt A, Colombo G (1998) Locomotor pattern in paraplegic patients: training effects and recov¬ery of spinal cord function. Spinal Cord 36: 380-390.
• Dietz V, Nakazawa K, Wirz M, Erni T (1999) Level of spinal cord lesion determines locomotor activity in spinal man. Exp Brain Res 128: 405-409.
• Dobkin BH (2000) Spinal and supraspinal plasticity after incomplete spinal cord injury: correlations between func¬tional magnetic resonance imaging and engaged locomo¬tor networks. Prog Brain Res 128: 99-111.
• Dobkin BH, Harkema S, Requejo P, Edgerton VR (1995) Modulation of locomotor-like EMG activity in subjects with complete and incomplete spinal cord injury. J Neurol Rehabil 9: 183-190.
• Dreyfus CF, Dai X, Lercher LD, Racey BR, Friedman WJ, Black IB (1999) Expression of neurotrophins in the adult spinal cord in vivo. J Neurosci Res 56: 1-7.
• Dupont-Versteegden EE, Houle JD, Dennis RA, Zhang J, Knox M, Wagoner G, Peterson CA (2004) Exercise-induced gene expression in soleus muscle is dependent on time after spinal cord injury in rats. Muscle Nerve 29: 73-81.
• Emmert-Buck MR, Bonner RF, Smith PD, Chuaqui RF, Zhuang Z, Goldstein SR, Weiss RA, Liotta LA (1996) Laser capture microdissection. Science 274: 998-1001.
• Farooque M, Hillered L, Holtz A, Olsson Y (1996) Changes of extracellular levels of amino acids after graded compres¬sion trauma to the spinal cord: an experimental study in the rat using microdialysis. J Neurotrauma 13: 537-548.
• Feng J, Fouse S, Fan G (2007) Epigenetic regulation of neu¬ral gene expression and neuronal function. Pediatr Res 61: 58R-63R.
• Fernyhough P, Diemel LT, Brewster WJ, Tomlinson DR (1995) Altered neurotrophin mRNA levels in peripheral nerve and skeletal muscle of experimentally diabetic rats. J Neurochem 64: 1231-1237.
• Ferris LT, Williams JS, Shen CL (2007) The effect of acute exercise on serum brain-derived neurotrophic factor levels and cognitive function. Med Sci Sports Exerc 39: 728-734.
• Fortun J, Puzis R, Pearse DD, Gage FH, Bunge MB (2009) Muscle injection of AAV-NT3 promotes anatomical reor¬ganization of CST axons and improves behavioral out¬come following SCI. J Neurotrauma 26: 941-953.
• Friedman B, Kleinfeld D, Ip NY, Verge VM, Moulton R, Boland P, Zlotchenko E, Lindsay RM, Liu L (1995) BDNF and NT-4/5 exert neurotrophic influences on injured adult spinal motor neurons. J Neurosci 15: 1044-1056.
• Frisen J, Verge VM, Cullheim S, Persson H, Fried K, Middlemas DS, Hunter T, Hokfelt T, Risling M (1992) Increased levels of trkB mRNA and trkB protein-like immunoreactivity in the injured rat and cat spinal cord. Proc Natl Acad Sci U S A 89: 11282-11286.
• Gajewska-Wozniak O, Skup M, Kasicki S, Ziemlinska E, Czarkowska-Bauch J (2013) Enhancing proprioceptive input to motoneurons differentially affects expression of neurotrophin 3 and brain-derived neurotrophic factor in rat hoffmann-reflex circuitry. PloS One 8:e65937.
• Garcia N, Tomas M, Santafe MM, Besalduch N, Lanuza MA, Tomas J (2010a) The interaction between tropomyosin- related kinase B receptors and presynaptic muscarinic receptors modulates transmitter release in adult rodent motor nerve terminals. J Neurosci 30: 16514-16522.
• Garcia N, Tomas M, Santafe MM, Lanuza MA, Besalduch N, Tomas J (2010b) Localization of brain-derived neu¬rotrophic factor, neurotrophin-4, tropomyosin-related kinase b receptor, and p75 NTR receptor by high-resolu¬tion immunohistochemistry on the adult mouse neuro¬muscular junction. J Peripher Nerv Syst 15: 40-49.
• Gazula VR, Roberts M, Luzzio C, Jawad AF, Kalb RG (2004) Effects of limb exercise after spinal cord injury on motor neuron dendrite structure. J Comp Neurol 476: 130-145.
• Goda A, Ohgi S, Kinpara K, Shigemori K, Fukuda K, Schneider EB (2013) Changes in serum BDNF levels associated with moderate-intensity exercise in healthy young Japanese men. Springerplus 2: 678.
• Gomez-Pinilla F, Ying Z, Opazo P, Roy RR, Edgerton VR (2001) Differential regulation by exercise of BDNF and NT-3 in rat spinal cord and skeletal muscle. Eur J Neurosci 13: 1078-1084.
• Gomez-Pinilla F, Ying Z, Roy RR, Molteni R, Edgerton VR (2002) Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J Neurophysiol 88: 2187-2195.
• Gomez-Pinilla F, Ying Z, Roy RR, Hodgson J, Edgerton VR (2004) Afferent input modulates neurotrophins and syn- aptic plasticity in the spinal cord. J Neurophysiol 92: 3423-3432.
• Gomez-Pinilla F, Zhuang Y, Feng J, Ying Z, Fan G (2011) Exercise impacts brain-derived neurotrophic factor plas¬ticity by engaging mechanisms of epigenetic regulation. Eur J Neurosci 33: 383-390.
• Gorassini MA, Bennett DJ, Yang JF (1998) Self-sustained firing of human motor units. Neurosci Lett 247: 13-16.
• Grasso R, Ivanenko YP, Zago M, Molinari M, Scivoletto G, Castellano V, Macellari V, Lacquaniti F (2004) Distributed plasticity of locomotor pattern generators in spinal cord injured patients. Brain 127: 1019-1034.
• Greenberg ME, Xu B, Lu B, Hempstead BL (2009) New insights in the biology of BDNF synthesis and release: implications in CNS function. J Neurosci 29: 12764¬12767.
• Griesbeck O, Parsadanian AS, Sendtner M, Thoenen H (1995) Expression of neurotrophins in skeletal muscle: quantitative comparison and significance for motoneuron survival and maintenance of function. J Neurosci Res 42: 21-33.
• Grill RJ, Blesch A, Tuszynski MH (1997) Robust growth of chronically injured spinal cord axons induced by grafts of genetically modified NGF-secreting cells. Exp Neurol 148: 444-452.
• Grunnet M, Jespersen T, Perrier JF (2004) 5-HT1A receptors modulate small-conductance Ca2+-activated K+ chan¬nels. J Neurosci Res 78: 845-854.
• Hadjiconstantinou M, Panula P, Lackovic Z, Neff NH (1984) Spinal cord serotonin: a biochemical and immunohis- tochemical study following transection. Brain Res 322: 245-254.
• Harkema SJ, Hurley SL, Patel UK, Requejo PS, Dobkin BH, Edgerton VR (1997) Human lumbosacral spinal cord interprets loading during stepping. J Neurophysiol 77: 797-811.
• Harvey PJ, Li X, Li Y, Bennett DJ (2006) 5-HT2 receptor activation facilitates a persistent sodium current and repetitive firing in spinal motoneurons of rats with and without chronic spinal cord injury. J Neurophysiol 96: 1158-1170.
• Hensbergen E, Kernell D (1997) Daily durations of sponta¬neous activity in cat's ankle muscles. Exp Brain Res 115: 325-332.
• Higuchi H, Yamashita T, Yoshikawa H, Tohyama M (2003) PKA phosphorylates the p75 receptor and regulates its localization to lipid rafts. EMBO J 22: 1790-1800.
• Holm NR, Christophersen P, Olesen SP, Gammeltoft S (1997) Activation of calcium-dependent potassium chan¬nels in mouse [correction of rat] brain neurons by neu- rotrophin-3 and nerve growth factor. Proc Natl Acad Sci U S A 94: 1002-1006.
• Houle JD, Côté MP (2013) Axon regeneration and exercise- dependent plasticity after spinal cord injury. Ann N Y Acad Sci 1279: 154-163.
• Hounsgaard J, Kiehn O (1989) Serotonin-induced bistability of turtle motoneurones caused by a nifedipine-sensitive calcium plateau potential. J Physiol 414: 265-282.
• Ichiyama RM, Broman J, Roy RR, Zhong H, Edgerton VR, Havton LA (2011) Locomotor training maintains normal inhibitory influence on both alpha- and gamma-motoneu- rons after neonatal spinal cord transection. J Neurosci 31: 26-33.
• Ilha J, Centenaro LA, Broetto Cunha N, de Souza DF, Jaeger M, do Nascimento PS, Kolling J, Ben J, Marcuzzo S, Wyse AT, Gottfried C, Achaval M (2011) The beneficial effects of treadmill step training on activity-dependent synaptic and cellular plasticity markers after complete spinal cord injury. Neurochem Res 36: 1046-1055.
• Jacob JE, Pniak A, Weaver LC, Brown A (2001) Autonomic dysreflexia in a mouse model of spinal cord injury. Neuroscience 108: 687-693.
• Kaila K (1994) Ionic basis of GABAA receptor channel function in the nervous system. Prog Neurobiol 42: 489¬537.
• Keeler BE, Liu G, Siegfried RN, Zhukareva V, Murray M, Houle JD (2012) Acute and prolonged hindlimb exercise elicits different gene expression in motoneurons than sensory neurons after spinal cord injury. Brain Res 1438: 8-21.
• Khristy W, Ali NJ, Bravo AB, de Leon R, Roy RR, Zhong H, London NJ, Edgerton VR, Tillakaratne NJ (2009) Changes in GABA(A) receptor subunit gamma 2 in extensor and flexor motoneurons and astrocytes after spinal cord transection and motor training. Brain Res 1273: 9-17.
• Kiehn O (2006) Locomotor circuits in the mammalian spinal cord. Ann Rev Neurosci 29: 279-306.
• Kiehn O, Eken T (1997) Prolonged firing in motor units: evidence of plateau potentials in human motoneurons? J Neurophysiol 78: 3061-3068.
• Kitzman P (2005) Alteration in axial motoneuronal mor¬phology in the spinal cord injured spastic rat. Exp Neurol 192: 100-108.
• Kitzman P (2006) Changes in vesicular glutamate trans¬porter 2, vesicular GABA transporter and vesicular ace- tylcholine transporter labeling of sacrocaudal motoneu- rons in the spastic rat. Exp Neurol 197: 407-419.
• Koliatsos VE, Clatterbuck RE, Winslow JW, Cayouette MH, Price DL (1993) Evidence that brain-derived neurotrophic factor is a trophic factor for motor neurons in vivo. Neuron 10: 359-367.
• Kong XY, Wienecke J, Hultborn H, Zhang M (2010) Robust upregulation of serotonin 2A receptors after chronic spi¬nal transection of rats: an immunohistochemical study. Brain Res 1320: 60-68.
• Krenz NR, Meakin SO, Krassioukov AV, Weaver LC (1999) Neutralizing intraspinal nerve growth factor blocks auto- nomic dysreflexia caused by spinal cord injury. J Neurosci 19: 7405-7414.
• Kubasak MD, Jindrich DL, Zhong H, Takeoka A, McFarland KC, Munoz-Quiles C, Roy RR, Edgerton VR, Ramon- Cueto A, Phelps PE (2008) OEG implantation and step training enhance hindlimb-stepping ability in adult spinal transected rats. Brain 131: 264-276.
• Kuczewski N, Porcher C, Lessmann V, Medina I, Gaiarsa JL (2009) Activity-dependent dendritic release of BDNF and biological consequences. Mol Neurobiol 39: 37-49.
• Lee FS, Chao MV (2001) Activation of Trk neurotrophin receptors in the absence of neurotrophins. Proc Natl Acad Sci U S A 98: 3555-3560.
• Lessmann V, Gottmann K, Malcangio M (2003) Neurotrophin secretion: current facts and future prospects. Prog Neurobiol 69: 341-374.
• Li Y, Gorassini MA, Bennett DJ (2004) Role of persistent sodium and calcium currents in motoneuron firing and spasticity in chronic spinal rats. J Neurophysiol 91: 767¬783.
• Macias M, Fehr S, Dwornik A, Sulejczak D, Wiater M, Czarkowska-Bauch J, Skup M, Schachner M (2002) Exercise increases mRNA levels for adhesion molecules N-CAM and L1 correlating with BDNF response. Neuroreport 13: 2527-2530.
• Macias M, Dwornik A, Skup M, Czarkowska-Bauch J (2005) Confocal visualization of the effect of short-term locomotor exercise on BDNF and TrkB distribution in the lumbar spinal cord of the rat: the enhancement of BDNF in dendrites? Acta Neurobiol Exp (Wars) 65: 177-182.
• Macias M, Dwornik A, Ziemlinska E, Fehr S, Schachner M, Czarkowska-Bauch J, Skup M (2007) Locomotor exer¬cise alters expression of pro-BDNF, BDNF and its recep¬tor TrkB in the spinal cord of adult rats. Eur J Neurosci 25: 2425-2444.
• Macias M, Nowicka D, Czupryn A, Sulejczak D, Skup M, Skangiel-Kramska J, Czarkowska-Bauch J (2009) Exercise-induced motor improvement after complete spi¬nal cord transection and its relation to expression of brain-derived neurotrophic factor and presynaptic mark¬ers. BMC Neurosci 10: 144.
• Maciejewska A (2013) An impact of complete spinal cord transection and locomotor training on glycinergic inner¬vation of ventral horn neurons of the spinal cord in adult rats. MSc thesis (in Polish). Faculty of Horticulture, Biotechnology and Landscape Architecture, Warsaw University of Life Sciences, Warsaw, PL.
• Magnusson T (1973) Effect of chronic transection on dop¬amine, noradrenaline and 5-hydroxytryptamine in the rat spinal cord. Naunyn Schmiedebergs Arch Pharmacol 278: 13-22.
• Mantilla CB, Zhan WZ, Sieck GC (2004) Neurotrophins improve neuromuscular transmission in the adult rat dia¬phragm. Muscle Nerve 29: 381-386.
• Marsh DR, Wong ST, Meakin SO, MacDonald JI, Hamilton EF, Weaver LC (2002) Neutralizing intraspinal nerve growth factor with a trkA-IgG fusion protein blocks the development of autonomic dysreflexia in a clip-compres¬sion model of spinal cord injury. J Neurotrauma 19: 1531-1541.
• Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y, Fan G, Sun YE (2003) DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302: 890-893.
• Menei P, Montero-Menei C, Whittemore SR, Bunge RP, Bunge MB (1998) Schwann cells genetically modified to secrete human BDNF promote enhanced axonal regrowth across transected adult rat spinal cord. Eur J Neurosci 10: 607-621.
• Miles GB, Hartley R, Todd AJ, Brownstone RM (2007) Spinal cholinergic interneurons regulate the excitability of motoneurons during locomotion. Proc Natl Acad Sci U S A 104: 2448-2453.
• Muennich EA, Fyffe RE (2004) Focal aggregation of volt¬age-gated, Kv2.1 subunit-containing, potassium channels at synaptic sites in rat spinal motoneurones. J Physiol 554: 673-685.
• Munson JB, Shelton DL, McMahon SB (1997) Adult mam¬malian sensory and motor neurons: roles of endogenous neurotrophins and rescue by exogenous neurotrophins after axotomy. J Neurosci 17: 470-476.
• Murakami Y, Furukawa S, Nitta A, Furukawa Y (2002) Accumulation of nerve growth factor protein at both ros¬tral and caudal stumps in the transected rat spinal cord. J Neurol Sci 198: 63-69.
• Murray KC, Nakae A, Stephens MJ, Rank M, D'Amico J, Harvey PJ, Li X, Harris RL, Ballou EW, Anelli R, Heckman CJ, Mashimo T, Vavrek R, Sanelli L, Gorassini MA, Bennett DJ, Fouad K (2010) Recovery of motoneu¬ron and locomotor function after spinal cord injury depends on constitutive activity in 5-HT2C receptors. Nat Med 16: 694-700.
• Murray KC, Stephens MJ, Rank M, D'Amico J, Gorassini MA, Bennett DJ (2011) Polysynaptic excitatory postsyn- aptic potentials that trigger spasms after spinal cord injury in rats are inhibited by 5-HT1B and 5-HT1F recep¬tors. J Neurophysiol 106: 925-943.
• Murray M, Fischer I, Smeraski C, Tessler A, Giszter S (2004) Towards a definition of recovery of function. J Neurotrauma 21: 405-413.
• Nagappan G, Lu B (2005) Activity-dependent modulation of the BDNF receptor TrkB: mechanisms and implications. Trends Neurosci 28: 464-471.
• Naito KS, Ichiyama T, Kawakami S, Kadoya M, Tabata T, Matsuda M, Ikeda S (2008) AL amyloidosis with sponta¬neous hepatic rupture: successful treatment by transcath- eter hepatic artery embolization. Amyloid 15: 137-139.
• Navarrett S, Collier L, Cardozo C, Dracheva S (2012) Alterations of serotonin 2C and 2A receptors in response to T10 spinal cord transection in rats. Neurosci Lett 506: 74-78.
• Newton BW, Hamill RW (1988) The morphology and distri¬bution of rat serotoninergic intraspinal neurons: an immu- nohistochemical study. Brain Res Bull 20: 349-360.
• Newton BW, Maley BE, Hamill RW (1986) Immunohistochemical demonstration of serotonin neu¬rons in autonomic regions of the rat spinal cord. Brain Res 376: 155-163.
• Ngo-Anh TJ, Bloodgood BL, Lin M, Sabatini BL, Maylie J, Adelman JP (2005) SK channels and NMDA receptors form a Ca2+-mediated feedback loop in dendritic spines. Nat Neurosci 8: 642-649.
• Novikov LN, Novikova LN, Holmberg P, Kellerth J (2000) Exogenous brain-derived neurotrophic factor regulates the synaptic composition of axonally lesioned and normal adult rat motoneurons. Neuroscience 100: 171-181.
• Ollivier-Lanvin K, Keeler BE, Siegfried R, Houle JD, Lemay MA (2010) Proprioceptive neuropathy affects normalization of the H-reflex by exercise after spinal cord injury. Experimental neurology 221: 198-205.
• Panter SS, Yum SW, Faden AI (1990) Alteration in extracel¬lular amino acids after traumatic spinal cord injury. Ann Neurol 27: 96-99.
• Patel TD, Kramer I, Kucera J, Niederkofler V, Jessell TM, Arber S, Snider WD (2003) Peripheral NT3 signaling is required for ETS protein expression and central pattern¬ing of proprioceptive sensory afferents. Neuron 38: 403¬416.
• Payne JA, Rivera C, Voipio J, Kaila K (2003) Cation- chloride co-transporters in neuronal communication, development and trauma. Trends Neurosci 26: 199-206.
• Pereira DB, Chao MV (2007) The tyrosine kinase Fyn deter¬mines the localization of TrkB receptors in lipid rafts. J Neurosci 27: 4859-4869.
• Petruska JC, Ichiyama RM, Jindrich DL, Crown ED, Tansey KE, Roy RR, Edgerton VR, Mendell LM (2007) Changes in motoneuron properties and synaptic inputs related to step training after spinal cord transection in rats. J Neurosci 27: 4460-4471.
• Piehl F, Frisen J, Risling M, Hokfelt T, Cullheim S (1994) Increased trkB mRNA expression by axotomized motoneurones. Neuroreport 5: 697-700.
• Płatek R (2014) Influence of L1-CAM overexpression in tha rat spinal cord on injury induced alterations in neu- rotransmitters system and proteins engaged in neuronal network reorganization (PhD thesis) (in Polish). Department of Neurophysiology, Nencki Institute of Experimental Biology, PAS, Warsaw, PL.
• Poo MM (2001) Neurotrophins as synaptic modulators. Nat Rev Neurosci 2: 24-32.
• Raineteau O, Schwab ME (2001) Plasticity of motor sys¬tems after incomplete spinal cord injury. Nat Rev Neurosci 2: 263-273.
• Ramer MS, Priestley JV, McMahon SB (2000) Functional regeneration of sensory axons into the adult spinal cord. Nature 403: 312-316.
• Razin A (1998) CpG methylation, chromatin structure and gene silencing-a three-way connection. EMBO J 17: 4905-4908.
• Ren LQ, Wienecke J, Chen M, Moller M, Hultborn H, Zhang M (2013) The time course of serotonin 2C receptor expression after spinal transection of rats: an immunohis- tochemical study. Neuroscience 236: 31-46.
• Rind HB, Butowt R, von Bartheld CS (2005) Synaptic target¬ing of retrogradely transported trophic factors in motoneu- rons: comparison of glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, and cardiotro- phin-1 with tetanus toxin. J Neurosci 25: 539-549.
• Rizzoli AA (1968) Distribution of glutamic acid, aspartic acid, gamma-aminobutyric acid and glycine in six areas of cat spinal cord before and after transection. Brain Res 11: 11-18.
• Robinson GA, Goldberger ME (1986) The development and recovery of motor function in spinal cats. II. Pharmacological enhancement of recovery. Exp Brain Res 62: 387-400.
• Romero MI, Rangappa N, Li L, Lightfoot E, Garry MG, Smith GM (2000) Extensive sprouting of sensory affer¬ents and hyperalgesia induced by conditional expression of nerve growth factor in the adult spinal cord. J Neurosci 20: 4435-4445.
• Romero MI, Rangappa N, Garry MG, Smith GM (2001) Functional regeneration of chronically injured sensory afferents into adult spinal cord after neurotrophin gene therapy. J Neurosci 21: 8408-8416.
• Rong R, Meng BL, Jiang N, Hu LQ, Wang TH (2011) Roles of BDNF in spinal neuroplasticity in cats subjected to par¬tial dorsal ganglionectomy. Growth Factors 29: 263-270.
• Rose CR, Blum R, Kafitz KW, Kovalchuk Y, Konnerth A (2004) From modulator to mediator: rapid effects of BDNF on ion channels. Bioessays 26: 1185-1194.
• Rossignol S, Brustein E, Bouyer L, Barthelemy D, Langlet C, Leblond H (2004) Adaptive changes of locomotion after central and peripheral lesions. Can J Physiol Pharmacol 82: 617-627.
• Rothberg BS (2012) The BK channel: a vital link between cellular calcium and electrical signaling. Protein Cell 3: 883-892.
• Roudet C, Mouchet P, Feuerstein C, Savasta M (1994) Normal distribution of alpha 2-adrenoceptors in the rat spinal cord and its modification after noradrenergic den- ervation: a quantitative autoradiographic study. J Neurosci Res 39: 319-329.
• Roux S, Saint Cloment C, Curie T, Girard E, Mena FJ, Barbier J, Osta R, Molgo J, Brulet P (2006) Brain-derived neurotrophic factor facilitates in vivo internalization of tetanus neurotoxin C-terminal fragment fusion proteins in mature mouse motor nerve terminals. Eur J Neurosci 24: 1546-1554.
• Roy RR, Talmadge RJ, Hodgson JA, Oishi Y, Baldwin KM, Edgerton VR (1999) Differential response of fast hindlimb extensor and flexor muscles to exercise in adult spinal- ized cats. Muscle Nerve 22: 230-241.
• Roy RR, Zhong H, Khalili N, Kim SJ, Higuchi N, Monti RJ, Grossman E, Hodgson JA, Edgerton VR (2007) Is spinal cord isolation a good model of muscle disuse? Muscle Nerve 35: 312-321.
• Sartini S, Bartolini F, Ambrogini P, Betti M, Ciuffoli S, Lattanzi D, Di Palma M, Cuppini R (2013) Motor activity affects adult skeletal muscle re-innervation acting via tyrosine kinase receptors. Eur J Neurosci 37: 1394-1403.
• Scarisbrick IA, Isackson PJ, Windebank AJ (1999) Differential expression of brain-derived neurotrophic fac¬tor, neurotrophin-3, and neurotrophin-4/5 in the adult rat spinal cord: regulation by the glutamate receptor agonist kainic acid. J Neurosci 19: 7757-7769.
• Schmolesky MT, Webb DL, Hansen RA (2013) The effects of aerobic exercise intensity and duration on levels of brain-derived neurotrophic factor in healthy men. J Sports Sci Med 12: 502-511.
• Sheean G (2002) The pathophysiology of spasticity. Eur J Neurol 9 (Suppl 1): 3-9; dicussion 53-61.
• Sherrington CS (1910) Flexion-reflex of the limb, crossed extension-reflex, and reflex stepping and standing. J Physiol 40: 28-121.
• Skup M, Dwornik A, Macias M, Sulejczak D, Wiater M, Czarkowska-Bauch J (2002) Long-term locomotor train¬ing up-regulates TrkB(FL) receptor-like proteins, brain- derived neurotrophic factor, and neurotrophin 4 with dif¬ferent topographies of expression in oligodendroglia and neurons in the spinal cord. Exp Neurol 176: 289-307.
• Skup M, Wiater M, Gornicka E, Walentynowicz M, Czarkowska-Bauch J (2007) Different effect of locomotor exercise on the homogenate concentration of amino acids and monoamines in the rostral and caudal lumbar segments of the spinal cord in the rat. Spinal Cord 45: 140-148.
• Skup M, Ziemlinska E, Wewior I, Grygielewicz P, Czarkowska-Bauch J, Kugler S (2011) AAV-mediated BDNF overexpression does not down-regulate TrkFL and
• TrkTK receptors in the transected spinal cord of the rat. IBRO-ESN 23-rd Biennial Meeting Athens. J Neurochemistry 118: 81.
• Skup M, Gajewska-Wozniak O, Grygielewicz P, Mankovskaya T, Czarkowska-Bauch J (2012) Different effects of spinalization and locomotor training of spinal animals on cholinergic innervation of the soleus and tibi¬alis anterior motoneurons. Eur J Neurosci 36: 2679¬2688.
• Stanton ES, Smolen PM, Nashold BS, Jr., Dreyer DA, Davis JN (1975) Segmental analysis of spinal cord monoamines after thoracic transection in the dog. Brain Res 89: 93-98.
• Stepien AE, Tripodi M, Arber S (2010) Monosynaptic rabies virus reveals premotor network organization and synaptic specificity of cholinergic partition cells. Neuron 68: 456-472.
• Suzuki S, Numakawa T, Shimazu K, Koshimizu H, Hara T, Hatanaka H, Mei L, Lu B, Kojima M (2004) BDNF- induced recruitment of TrkB receptor into neuronal lipid rafts: roles in synaptic modulation. J Cell Biol 167: 1205-1215.
• Takeoka A, Kubasak MD, Zhong H, Roy RR, Phelps PE (2009) Serotonergic innervation of the caudal spinal stump in rats after complete spinal transection: effect of olfactory ensheathing glia. J Comp Neurol 515: 664¬676.
• Takeoka A, Kubasak MD, Zhong H, Kaplan J, Roy RR, Phelps PE (2010) Noradrenergic innervation of the rat spinal cord caudal to a complete spinal cord transection: effects of olfactory ensheathing glia. Exp Neurol 222: 59-69.
• Talmadge RJ, Roy RR, Caiozzo VJ, Edgerton VR (2002) Mechanical properties of rat soleus after long-term spinal cord transection. J Appl Physiol (1985) 93: 1487-1497.
• Thompson SM, Gahwiler BH (1989) Activity-dependent disinhibition. II. Effects of extracellular potassium, furo- semide, and membrane potential on ECl- in hippocampal CA3 neurons. J Neurophysiol 61: 512-523.
• Tian F, Marini AM, Lipsky RH (2010) Effects of histone deacetylase inhibitor Trichostatin A on epigenetic changes and transcriptional activation of Bdnf promoter 1 by rat hippocampal neurons. Ann N Y Acad Sci 1199: 186-193.
• Tillakaratne NJ, Mouria M, Ziv NB, Roy RR, Edgerton VR, Tobin AJ (2000) Increased expression of glutamate decar- boxylase (GAD(67)) in feline lumbar spinal cord after complete thoracic spinal cord transection. J Neurosci Res 60: 219-230.
• Tillakaratne NJ, de Leon RD, Hoang TX, Roy RR, Edgerton VR, Tobin AJ (2002) Use-dependent modulation of inhibitory capacity in the feline lumbar spinal cord. J Neurosci 22: 3130-3143.
• Tillakaratne NJ, Guu JJ, de Leon RD, Bigbee AJ, London NJ, Zhong H, Ziegler MD, Joynes RL, Roy RR, Edgerton VR (2010) Functional recovery of stepping in rats after a com¬plete neonatal spinal cord transection is not due to regrowth across the lesion site. Neuroscience 166: 23-33.
• Tolwani RJ, Cosgaya JM, Varma S, Jacob R, Kuo LE, Shooter EM (2004) BDNF overexpression produces a long-term increase in myelin formation in the peripheral nervous system. J Neurosci Res 77: 662-669.
• Toyoda H, Ohno K, Yamada J, Ikeda M, Okabe A, Sato K, Hashimoto K, Fukuda A (2003) Induction of NMDA and GABAA receptor-mediated Ca2+ oscillations with KCC2 mRNA downregulation in injured facial motoneurons. J Neurophysiol 89: 1353-1362.
• Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ (2006) Sustained hippocampal chromatin reg¬ulation in a mouse model of depression and antidepres- sant action. Nat Neurosci 9: 519-525.
• Tuszynski MH, Gabriel K, Gage FH, Suhr S, Meyer S, Rosetti A (1996) Nerve growth factor delivery by gene transfer induces differential outgrowth of sensory, motor, and noradrenergic neurites after adult spinal cord injury. Exp Neurol 137: 157-173.
• Wainberg M, Barbeau H, Gauthier S (1990) The effects of cyproheptadine on locomotion and on spasticity in patients with spinal cord injuries. J Neurol Neurosurg Psychiatry 53: 754-763.
• Wang XH, Poo MM (1997) Potentiation of developing syn¬apses by postsynaptic release of neurotrophin-4. Neuron 19: 825-835.
• Wang X, Berninger B, Poo M (1998) Localized synaptic actions of neurotrophin-4. J Neurosci 18: 4985-4992.
• Wernig A, Muller S, Nanassy A, Cagol E (1995) Laufband therapy based on 'rules of spinal locomotion' is effective in spinal cord injured persons. Eur J Neurosci 7: 823-829.
• Widenfalk J, Olson L, Thorén P (1999) Deprived of habitual running, rats downregulate BDNF and TrkB messages in the brain. Neurosci Res 34: 125-132.
• Widenfalk J, Lundstromer K, Jubran M, Brene S, Olson L (2001) Neurotrophic factors and receptors in the imma¬ture and adult spinal cord after mechanical injury or kainic acid. J Neurosci 21: 3457-3475.
• Wienecke J, Westerdahl AC, Hultborn H, Kiehn O, Ryge J (2010) Global gene expression analysis of rodent motor neurons following spinal cord injury associates molecular mechanisms with development of postinjury spasticity. J Neurophysiol 103: 761-778.
• Wilson JM, Rempel J, Brownstone RM (2004) Postnatal development of cholinergic synapses on mouse spinal motoneurons. J Comp Neurol 474: 13-23.
• Wong AW, Xiao J, Kemper D, Kilpatrick TJ, Murray SS (2013) Oligodendroglial expression of TrkB indepen¬dently regulates myelination and progenitor cell prolifer¬ation. J Neurosci 33: 4947-4957.
• Woodrow L, Sheppard P, Gardiner PF (2013) Transcriptional changes in rat a-motoneurons resulting from increased physical activity. Neuroscience 255: 45-54.
• Xiao J, Wong AW, Willingham MM, van den Buuse M, Kilpatrick TJ, Murray SS (2010) Brain-derived neu¬rotrophic factor promotes central nervous system myeli- nation via a direct effect upon oligodendrocytes. Neurosignals 18: 186-202.
• Yan Q, Elliott JL, Matheson C, Sun J, Zhang L, Mu X, Rex KL, Snider WD (1993) Influences of neurotrophins on mammalian motoneurons in vivo. J Neurobiol 24: 1555¬1577.
• Ying B, Lu N, Zhang YQ, Zhao ZQ (2006) Involvement of spinal glia in tetanically sciatic stimulation-induced bilat¬eral mechanical allodynia in rats. Biochem Biophys Res Commun 340: 1264-1272.
• Zagoraiou L, Akay T, Martin JF, Brownstone RM, Jessell TM, Miles GB (2009) A cluster of cholinergic premotor interneurons modulates mouse locomotor activity. Neuron 64: 645-662.
• Zhao C, Veltri K, Li S, Bain JR, Fahnestock M (2004) NGF, BDNF, NT-3, and GDNF mRNA expression in rat skele¬tal muscle following denervation and sensory protection. J Neurotrauma 21: 1468-1478.
• Ziemlińska E, Maciejewska A, Płatek R, Gajewska- Woźniak O, Czarkowska-Bauch J, Skup M (2013) Spinal cord transection leads to attenuation of determi¬nants of GABAergic and glycinergic transmission not accompanied by changes in inhibitory inputs to motoneu¬rons. 11th International Congress of Polish Neuroscience Society. Acta Neurobiol Exp (Wars) 73 (Suppl.): 36.
• Ziemlińska E, Kügler S, Schachner M, Wewiór I, Czarkowska-Bauch J, Skup M (2014) Overexpression of BDNF increases excitability of the lumbar spinal network and leads to robust early locomotor recovery in com¬pletely spinalized rats. PloS One 9:e88833.