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NO Orchestrates the Loss of Synaptic Boutons from Adult “Sick” Motoneurons: Modeling a Molecular Mechanism

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Abstract

Synapse elimination is the main factor responsible for the cognitive decline accompanying many of the neuropathological conditions affecting humans. Synaptic stripping of motoneurons is also a common hallmark of several motor pathologies. Therefore, knowledge of the molecular basis underlying this plastic process is of central interest for the development of new therapeutic tools. Recent advances from our group highlight the role of nitric oxide (NO) as a key molecule triggering synapse loss in two models of motor pathologies. De novo expression of the neuronal isoform of NO synthase (nNOS) in motoneurons commonly occurs in response to the physical injury of a motor nerve and in the course of amyotrophic lateral sclerosis. In both conditions, this event precedes synaptic withdrawal from motoneurons. Strikingly, nNOS-synthesized NO is “necessary” and “sufficient” to induce synaptic detachment from motoneurons. The mechanism involves a paracrine/retrograde action of NO on pre-synaptic structures, initiating a downstream signaling cascade that includes sequential activation of (1) soluble guanylyl cyclase, (2) cyclic guanosine monophosphate-dependent protein kinase, and (3) RhoA/Rho kinase (ROCK) signaling. Finally, ROCK activation promotes phosphorylation of regulatory myosin light chain, which leads to myosin activation and actomyosin contraction. This latter event presumably contributes to the contractile force to produce ending axon retraction. Several findings support that this mechanism may operate in the most prevalent neurodegenerative diseases.

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References

  1. Palop JJ, Chin J, Mucke L (2006) A network dysfunction perspective on neurodegenerative diseases. Nature 443:768–773

    CAS  PubMed  Google Scholar 

  2. Small DH (2008) Network dysfunction in Alzheimer's disease: does synaptic scaling drive disease progression? Trends Mol Med 14:103–108

    CAS  PubMed  Google Scholar 

  3. Scheff SW, Price DA (2006) Alzheimer's disease-related alterations in synaptic density: neocortex and hippocampus. J Alzheimers Dis 9:101–115

    PubMed  Google Scholar 

  4. Emre M (2003) Dementia associated with Parkinson's disease. Lancet Neurol 2:229–237

    CAS  PubMed  Google Scholar 

  5. Day M, Wang Z, Ding J et al (2006) Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models. Nat Neurosci 9:251–259

    CAS  PubMed  Google Scholar 

  6. Cepeda C, Wu N, Andre VM, Cummings DM, Levine MS (2007) The corticostriatal pathway in Huntington's disease. Prog Neurobiol 81:253–271

    CAS  PubMed  Google Scholar 

  7. Centonze D, Muzio L, Rossi S et al (2009) Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J Neurosci 29:3442–3452

    CAS  PubMed  Google Scholar 

  8. Kim HJ, Martemyanov KA, Thayer SA (2008) Human immunodeficiency virus protein Tat induces synapse loss via a reversible process that is distinct from cell death. J Neurosci 28:12604–12613

    CAS  PubMed  Google Scholar 

  9. Sasaki S, Maruyama S (1994) Synapse loss in anterior horn neurons in amyotrophic lateral sclerosis. Acta Neuropathol 88:222–227

    CAS  PubMed  Google Scholar 

  10. Ince PG, Slade J, Chinnery RM et al (1995) Quantitative study of synaptophysin immunoreactivity of cerebral cortex and spinal cord in motor neuron disease. J Neuropathol Exp Neurol 54:673–679

    CAS  PubMed  Google Scholar 

  11. Ikemoto A, Hirano A, Matsumoto S, Akiguchi I, Kimura J (1996) Synaptophysin expression in the anterior horn of Werdnig–Hoffmann disease. J Neurol Sci 136:94–100

    CAS  PubMed  Google Scholar 

  12. Ikemoto A, Kawanami T, Llena JF, Hirano A (1994) Immunocytochemical studies on synaptophysin in the anterior horn of lower motor neuron disease. J Neuropathol Exp Neurol 53:196–201

    CAS  PubMed  Google Scholar 

  13. Gonzalez-Forero D, Portillo F, Sunico CR, Moreno-Lopez B (2004) Nerve injury reduces responses of hypoglossal motoneurones to baseline and chemoreceptor-modulated inspiratory drive in the adult rat. J Physiol 557:991–1011

    CAS  PubMed  Google Scholar 

  14. Sunico CR, Portillo F, Gonzalez-Forero D, Moreno-Lopez B (2005) Nitric oxide-directed synaptic remodeling in the adult mammal CNS. J Neurosci 25:1448–1458

    CAS  PubMed  Google Scholar 

  15. Sunico CR, Gonzalez-Forero D, Dominguez G, Garcia-Verdugo JM, Moreno-Lopez B (2010) Nitric oxide induces pathological synapse loss by a protein kinase G-, Rho kinase-dependent mechanism preceded by myosin light chain phosphorylation. J Neurosci 30:973–984

    CAS  PubMed  Google Scholar 

  16. Moreno-Lopez B, Gonzalez-Forero D (2006) Nitric oxide and synaptic dynamics in the adult brain: physiopathological aspects. Rev Neurosci 17:309–357

    CAS  PubMed  Google Scholar 

  17. Sumner BE (1975) A quantitative analysis of boutons with different types of synapse in normal and injured hypoglossal nuclei. Exp Neurol 49:406–417

    CAS  PubMed  Google Scholar 

  18. Anneser JM, Cookson MR, Ince PG, Shaw PJ, Borasio GD (2001) Glial cells of the spinal cord and subcortical white matter up-regulate neuronal nitric oxide synthase in sporadic amyotrophic lateral sclerosis. Exp Neurol 171:418–421

    CAS  PubMed  Google Scholar 

  19. Catania MV, Aronica E, Yankaya B, Troost D (2001) Increased expression of neuronal nitric oxide synthase spliced variants in reactive astrocytes of amyotrophic lateral sclerosis human spinal cord. J Neurosci 21:RC148

    CAS  PubMed  Google Scholar 

  20. Sasaki S, Shibata N, Iwata M (2001) Neuronal nitric oxide synthase immunoreactivity in the spinal cord in amyotrophic lateral sclerosis. Acta Neuropathol 101:351–357

    CAS  PubMed  Google Scholar 

  21. Luth HJ, Holzer M, Gertz HJ, Arendt T (2000) Aberrant expression of nNOS in pyramidal neurons in Alzheimer's disease is highly co-localized with p21ras and p16INK4a. Brain Res 852:45–55

    CAS  PubMed  Google Scholar 

  22. Simic G, Lucassen PJ, Krsnik Z et al (2000) nNOS expression in reactive astrocytes correlates with increased cell death related DNA damage in the hippocampus and entorhinal cortex in Alzheimer's disease. Exp Neurol 165:12–26

    CAS  PubMed  Google Scholar 

  23. Fernandez-Vizarra P, Fernandez AP, Castro-Blanco S et al (2004) Expression of nitric oxide system in clinically evaluated cases of Alzheimer's disease. Neurobiol Dis 15:287–305

    CAS  PubMed  Google Scholar 

  24. Eve DJ, Nisbet AP, Kingsbury AE et al (1998) Basal ganglia neuronal nitric oxide synthase mRNA expression in Parkinson's disease. Brain Res Mol Brain Res 63:62–71

    CAS  PubMed  Google Scholar 

  25. Deckel AW, Tang V, Nuttal D, Gary K, Elder R (2002) Altered neuronal nitric oxide synthase expression contributes to disease progression in Huntington's disease transgenic mice. Brain Res 939:76–86

    CAS  PubMed  Google Scholar 

  26. Perez-Severiano F, Escalante B, Vergara P, Rios C, Segovia J (2002) Age-dependent changes in nitric oxide synthase activity and protein expression in striata of mice transgenic for the Huntington's disease mutation. Brain Res 951:36–42

    CAS  PubMed  Google Scholar 

  27. Zeis T, Probst A, Steck AJ, Stadelmann C, Bruck W, Schaeren-Wiemers N (2009) Molecular changes in white matter adjacent to an active demyelinating lesion in early multiple sclerosis. Brain Pathol 19:459–466

    CAS  PubMed  Google Scholar 

  28. Lee J, Ryu H, Ferrante RJ, Morris SM Jr, Ratan RR (2003) Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox. Proc Natl Acad Sci U S A 100:4843–4848

    CAS  PubMed  Google Scholar 

  29. Hill KE, Zollinger LV, Watt HE, Carlson NG, Rose JW (2004) Inducible nitric oxide synthase in chronic active multiple sclerosis plaques: distribution, cellular expression and association with myelin damage. J Neuroimmunol 151:171–179

    CAS  PubMed  Google Scholar 

  30. Broholm H, Andersen B, Wanscher B et al (2004) Nitric oxide synthase expression and enzymatic activity in multiple sclerosis. Acta Neurol Scand 109:261–269

    CAS  PubMed  Google Scholar 

  31. Kuljis RO, Shapshak P, Alcabes P, Rodriguez de la Vega P, Fujimura R, Petito CK (2002) Increased density of neurons containing NADPH diaphorase and nitric oxide synthase in the cerebral cortex of patients with HIV-1 infection and drug abuse. J NeuroAIDS 2:19–36

    PubMed  Google Scholar 

  32. Adamson DC, Wildemann B, Sasaki M et al (1996) Immunologic NO synthase: elevation in severe AIDS dementia and induction by HIV-1 gp41. Science 274:1917–1921

    CAS  PubMed  Google Scholar 

  33. Moreno-Lopez B (2010) Local isoform-specific NOS inhibition: a promising approach to promote motor function recovery after nerve injury. J Neurosci Res 88:1846–1857

    CAS  PubMed  Google Scholar 

  34. Holscher C (1997) Nitric oxide, the enigmatic neuronal messenger: its role in synaptic plasticity. Trends Neurosci 20:298–303

    CAS  PubMed  Google Scholar 

  35. Wu HH, Williams CV, McLoon SC (1994) Involvement of nitric oxide in the elimination of a transient retinotectal projection in development. Science 265:1593–1596

    CAS  PubMed  Google Scholar 

  36. Roskams AJ, Bredt DS, Dawson TM, Ronnett GV (1994) Nitric oxide mediates the formation of synaptic connections in developing and regenerating olfactory receptor neurons. Neuron 13:289–299

    CAS  PubMed  Google Scholar 

  37. Moreno-Lopez B, Estrada C, Escudero M (1998) Mechanisms of action and targets of nitric oxide in the oculomotor system. J Neurosci 18:10672–10679

    CAS  PubMed  Google Scholar 

  38. Moreno-Lopez B, Escudero M, De Vente J, Estrada C (2001) Morphological identification of nitric oxide sources and targets in the cat oculomotor system. J Comp Neurol 435:311–324

    CAS  PubMed  Google Scholar 

  39. Montero F, Portillo F, Gonzalez-Forero D, Moreno-Lopez B (2008) The nitric oxide/cyclic guanosine monophosphate pathway modulates the inspiratory-related activity of hypoglossal motoneurons in the adult rat. Eur J Neurosci 28:107–116

    PubMed  Google Scholar 

  40. Moreno-Lopez B, Escudero M, Delgado-Garcia JM, Estrada C (1996) Nitric oxide production by brain stem neurons is required for normal performance of eye movements in alert animals. Neuron 17:739–745

    CAS  PubMed  Google Scholar 

  41. Prast H, Philippu A (2001) Nitric oxide as modulator of neuronal function. Prog Neurobiol 64:51–68

    CAS  PubMed  Google Scholar 

  42. Mendell LM (1984) Modifiability of spinal synapses. Physiol Rev 64:260–324

    CAS  PubMed  Google Scholar 

  43. Titmus MJ, Faber DS (1990) Axotomy-induced alterations in the electrophysiological characteristics of neurons. Prog Neurobiol 35:1–51

    CAS  PubMed  Google Scholar 

  44. Sunico CR, Portillo F, Gonzalez-Forero D, Kasparov S, Moreno-Lopez B (2008) Evidence for a detrimental role of nitric oxide synthesized by endothelial nitric oxide synthase after peripheral nerve injury. Neuroscience 157:40–51

    CAS  PubMed  Google Scholar 

  45. Bridge PM, Ball DJ, Mackinnon SE et al (1994) Nerve crush injuries—a model for axonotmesis. Exp Neurol 127:284–290

    CAS  PubMed  Google Scholar 

  46. Sunderland S (1951) A classification of peripheral nerve injuries producing loss of function. Brain 74:491–516

    CAS  PubMed  Google Scholar 

  47. Vaughan DW (1994) Effects of peripheral axotomy on presynaptic axon terminals with GABA-like immunoreactivity. Anat Rec 238:248–262

    CAS  PubMed  Google Scholar 

  48. Soreide AJ (1981) Variations in the perineuronal glial changes after different types of nerve lesion: light and electron microscopic investigations on the facial nucleus of the rat. Neuropathol Appl Neurobiol 7:195–204

    CAS  PubMed  Google Scholar 

  49. Hamberger A, Hansson HA, Sjostrand J (1970) Surface structure of isolated neurons: detachment of nerve terminals during axon regeneration. J Cell Biol 47:319–331

    CAS  PubMed  Google Scholar 

  50. Johnson IP, Gowda CK, Sears TA, Hunter AS (1998) Differences in the synaptic complement of thoracic motoneurons of adult and ageing cats after permanent or reversible axotomy. Synapse 28:176–184

    CAS  PubMed  Google Scholar 

  51. Zelano J, Berg A, Thams S, Hailer NP, Cullheim S (2009) SynCAM1 expression correlates with restoration of central synapses on spinal motoneurons after two different models of peripheral nerve injury. J Comp Neurol 517:670–682

    CAS  PubMed  Google Scholar 

  52. Delgado-Garcia JM, Del Pozo F, Spencer RF, Baker R (1988) Behavior of neurons in the abducens nucleus of the alert cat—III. Axotomized motoneurons. Neuroscience 24:143–160

    CAS  PubMed  Google Scholar 

  53. Blinzinger K, Kreutzberg G (1968) Displacement of synaptic terminals from regenerating motoneurons by microglial cells. Z Zellforsch Mikrosk Anat 85:145–157

    CAS  PubMed  Google Scholar 

  54. Jones KJ, Durica TE, Jacob SK (1997) Gonadal steroid preservation of central synaptic input to hamster facial motoneurons following peripheral axotomy. J Neurocytol 26:257–266

    CAS  PubMed  Google Scholar 

  55. Yamada J, Hayashi Y, Jinno S et al (2008) Reduced synaptic activity precedes synaptic stripping in vagal motoneurons after axotomy. Glia 56:1448–1462

    PubMed  Google Scholar 

  56. Svensson M, Aldskogius H (1993) Synaptic density of axotomized hypoglossal motorneurons following pharmacological blockade of the microglial cell proliferation. Exp Neurol 120:123–131

    CAS  PubMed  Google Scholar 

  57. Johnston IP, Sears TA (1989) Ultrastructure of axotomized alpha and gamma motoneurons in the cat thoracic spinal cord. Neuropathol Appl Neurobiol 15:149–163

    CAS  PubMed  Google Scholar 

  58. Chen DH (1978) Qualitative and quantitative study of synaptic displacement in chromatolyzed spinal motoneurons of the cat. J Comp Neurol 177:635–664

    CAS  PubMed  Google Scholar 

  59. Brannstrom T, Kellerth JO (1998) Changes in synaptology of adult cat spinal alpha-motoneurons after axotomy. Exp Brain Res 118:1–13

    CAS  PubMed  Google Scholar 

  60. Zelano J, Wallquist W, Hailer NP, Cullheim S (2007) Down-regulation of mRNAs for synaptic adhesion molecules neuroligin-2 and -3 and synCAM1 in spinal motoneurons after axotomy. J Comp Neurol 503:308–318

    CAS  PubMed  Google Scholar 

  61. Kerns JM, Hinsman EJ (1973) Neuroglial response to sciatic neurectomy. II. Electron microscopy. J Comp Neurol 151:255–280

    CAS  PubMed  Google Scholar 

  62. Emirandetti A, Graciele Zanon R, Sabha M Jr, de Oliveira AL (2006) Astrocyte reactivity influences the number of presynaptic terminals apposed to spinal motoneurons after axotomy. Brain Res 1095:35–42

    CAS  PubMed  Google Scholar 

  63. Sabha M Jr, Emirandetti A, Cullheim S, De Oliveira AL (2008) MHC I expression and synaptic plasticity in different mice strains after axotomy. Synapse 62:137–148

    CAS  PubMed  Google Scholar 

  64. Simoes GF, Oliveira AL (2010) Alpha motoneurone input changes in dystrophic MDX mice after sciatic nerve transection. Neuropathol Appl Neurobiol 36:55–70

    CAS  PubMed  Google Scholar 

  65. Oliveira AL, Thams S, Lidman O et al (2004) A role for MHC class I molecules in synaptic plasticity and regeneration of neurons after axotomy. Proc Natl Acad Sci U S A 101:17843–17848

    CAS  PubMed  Google Scholar 

  66. 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

    CAS  PubMed  Google Scholar 

  67. Barbizan R, Oliveira AL (2010) Impact of acute inflammation on spinal motoneuron synaptic plasticity following ventral root avulsion. J Neuroinflammation 7:29

    PubMed  Google Scholar 

  68. Scorisa JM, Zanon RG, Freria CM, de Oliveira AL (2009) Glatiramer acetate positively influences spinal motoneuron survival and synaptic plasticity after ventral root avulsion. Neurosci Lett 451:34–39

    CAS  PubMed  Google Scholar 

  69. Rodrigues Hell RC, Silva Costa MM, Goes AM, Oliveira AL (2009) Local injection of BDNF producing mesenchymal stem cells increases neuronal survival and synaptic stability following ventral root avulsion. Neurobiol Dis 33:290–300

    CAS  PubMed  Google Scholar 

  70. Linda H, Cullheim S, Risling M (1992) A light and electron microscopic study of intracellularly HRP-labeled lumbar motoneurons after intramedullary axotomy in the adult cat. J Comp Neurol 318:188–208

    CAS  PubMed  Google Scholar 

  71. Linda H, Shupliakov O, Ornung G et al (2000) Ultrastructural evidence for a preferential elimination of glutamate-immunoreactive synaptic terminals from spinal motoneurons after intramedullary axotomy. J Comp Neurol 425:10–23

    CAS  PubMed  Google Scholar 

  72. Cull RE (1974) Role of nerve-muscle contact in maintaining synaptic connections. Exp Brain Res 20:307–310

    CAS  PubMed  Google Scholar 

  73. Lago N, Navarro X (2006) Correlation between target reinnervation and distribution of motor axons in the injured rat sciatic nerve. J Neurotrauma 23:227–240

    PubMed  Google Scholar 

  74. Conradi S, Kellerth JO, Berthold CH (1979) Electron microscopic studies of serially sectioned cat spinal alpha-motoneurons. II. A method for the description of architecture and synaptology of the cell body and proximal dendritic segments. J Comp Neurol 184:741–754

    CAS  PubMed  Google Scholar 

  75. Ornung G, Ottersen OP, Cullheim S, Ulfhake B (1998) Distribution of glutamate-, glycine- and GABA-immunoreactive nerve terminals on dendrites in the cat spinal motor nucleus. Exp Brain Res 118:517–532

    CAS  PubMed  Google Scholar 

  76. Gray EG (1959) Axo-somatic and axo-dendritic synapses of the cerebral cortex: an electron microscope study. J Anat 93:420–433

    CAS  PubMed  Google Scholar 

  77. Bodian D (1966) Electron microscopy: two major synaptic types on spinal motoneurons. Science 151:1093–1094

    CAS  PubMed  Google Scholar 

  78. Uchizono K (1965) Characteristics of excitatory and inhibitory synapses in the central nervous system of the cat. Nature 207:642–643

    CAS  PubMed  Google Scholar 

  79. Rotter A, Birdsall NJ, Burgen AS, Field PM, Raisman G (1977) Axotomy causes loss of muscarinic receptors and loss of synaptic contacts in the hypoglossal nucleus. Nature 266:734–735

    CAS  PubMed  Google Scholar 

  80. Svensson M, Tornqvist E, Aldskogius H, Cova JL (1991) Synaptic detachment from hypoglossal neurons after different types of nerve injury in the cat. J Hirnforsch 32:547–552

    CAS  PubMed  Google Scholar 

  81. Rosen DR, Siddique T, Patterson D et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62

    CAS  PubMed  Google Scholar 

  82. Durand J, Amendola J, Bories C, Lamotte d'Incamps B (2006) Early abnormalities in transgenic mouse models of amyotrophic lateral sclerosis. J Physiol Paris 99:211–220

    PubMed  Google Scholar 

  83. Pasinelli P, Brown RH (2006) Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci 7:710–723

    CAS  PubMed  Google Scholar 

  84. Gurney ME (1997) Transgenic animal models of familial amyotrophic lateral sclerosis. J Neurol 244(Suppl 2):S15–S20

    PubMed  Google Scholar 

  85. Gurney ME, Pu H, Chiu AY et al (1994) Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264:1772–1775

    CAS  PubMed  Google Scholar 

  86. Bendotti C, Calvaresi N, Chiveri L et al (2001) Early vacuolization and mitochondrial damage in motor neurons of FALS mice are not associated with apoptosis or with changes in cytochrome oxidase histochemical reactivity. J Neurol Sci 191:25–33

    CAS  PubMed  Google Scholar 

  87. Ferrucci M, Spalloni A, Bartalucci A et al (2009) A systematic study of brainstem motor nuclei in a mouse model of ALS, the effects of lithium. Neurobiol Dis 37(2):370–383

    PubMed  Google Scholar 

  88. Jiang M, Schuster JE, Fu R, Siddique T, Heckman CJ (2009) Progressive changes in synaptic inputs to motoneurons in adult sacral spinal cord of a mouse model of amyotrophic lateral sclerosis. J Neurosci 29:15031–15038

    CAS  PubMed  Google Scholar 

  89. Leichsenring A, Linnartz B, Zhu XR, Lubbert H, Stichel CC (2006) Ascending neuropathology in the CNS of a mutant SOD1 mouse model of amyotrophic lateral sclerosis. Brain Res 1096:180–195

    CAS  PubMed  Google Scholar 

  90. Martin LJ, Liu Z, Chen K et al (2007) Motor neuron degeneration in amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice: mechanisms of mitochondriopathy and cell death. J Comp Neurol 500:20–46

    CAS  PubMed  Google Scholar 

  91. Miana-Mena FJ, Munoz MJ, Yague G et al (2005) Optimal methods to characterize the G93A mouse model of ALS. Amyotroph Lateral Scler Other Motor Neuron Disord 6:55–62

    CAS  PubMed  Google Scholar 

  92. Chiu AY, Zhai P, Dal Canto MC et al (1995) Age-dependent penetrance of disease in a transgenic mouse model of familial amyotrophic lateral sclerosis. Mol Cell Neurosci 6:349–362

    CAS  PubMed  Google Scholar 

  93. Hayworth CR, Gonzalez-Lima F (2009) Pre-symptomatic detection of chronic motor deficits and genotype prediction in congenic B6.SOD1(G93A) ALS mouse model. Neuroscience 164:975–985

    CAS  PubMed  Google Scholar 

  94. Sunico CR, Dominguez G, Garcia-Verdugo JM, Osta R, Montero F, Moreno-Lopez B (2011) Reduction in the motoneuron inhibitory/excitatory synaptic ratio in an early-symptomatic mouse model of amyotrophic lateral sclerosis. Brain Pathol 21:1–15. doi:10.1111/j.1750-3639.2010.00417.x

    PubMed  Google Scholar 

  95. Cleveland DW, Rothstein JD (2001) From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat Rev Neurosci 2:806–819

    CAS  PubMed  Google Scholar 

  96. Van Den Bosch L, Van Damme P, Bogaert E, Robberecht W (2006) The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis. Biochim Biophys Acta 1762:1068–1082

    Google Scholar 

  97. Rao SD, Weiss JH (2004) Excitotoxic and oxidative cross-talk between motor neurons and glia in ALS pathogenesis. Trends Neurosci 27:17–23

    CAS  PubMed  Google Scholar 

  98. Rothstein JD (2009) Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann Neurol 65(Suppl 1):S3–S9

    CAS  PubMed  Google Scholar 

  99. Bensimon G, Lacomblez L, Meininger V (1994) A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med 330:585–591

    CAS  PubMed  Google Scholar 

  100. Hollmann M, Hartley M, Heinemann S (1991) Ca2+ permeability of KA-AMPA-gated glutamate receptor channels depends on subunit composition. Science 252:851–853

    CAS  PubMed  Google Scholar 

  101. Bendotti C, Tortarolo M, Suchak SK et al (2001) Transgenic SOD1 G93A mice develop reduced GLT-1 in spinal cord without alterations in cerebrospinal fluid glutamate levels. J Neurochem 79:737–746

    CAS  PubMed  Google Scholar 

  102. Bruijn LI, Becher MW, Lee MK et al (1997) ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18:327–338

    CAS  PubMed  Google Scholar 

  103. Fray AE, Ince PG, Banner SJ et al (1998) The expression of the glial glutamate transporter protein EAAT2 in motor neuron disease: an immunohistochemical study. Eur J Neurosci 10:2481–2489

    CAS  PubMed  Google Scholar 

  104. Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW (1995) Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 38:73–84

    CAS  PubMed  Google Scholar 

  105. Zhao P, Ignacio S, Beattie EC, Abood ME (2008) Altered presymptomatic AMPA and cannabinoid receptor trafficking in motor neurons of ALS model mice: implications for excitotoxicity. Eur J Neurosci 27:572–579

    PubMed  Google Scholar 

  106. Avossa D, Grandolfo M, Mazzarol F, Zatta M, Ballerini L (2006) Early signs of motoneuron vulnerability in a disease model system: characterization of transverse slice cultures of spinal cord isolated from embryonic ALS mice. Neuroscience 138:1179–1194

    CAS  PubMed  Google Scholar 

  107. Carunchio I, Mollinari C, Pieri M, Merlo D, Zona C (2008) GAB(A) receptors present higher affinity and modified subunit composition in spinal motor neurons from a genetic model of amyotrophic lateral sclerosis. Eur J Neurosci 28:1275–1285

    PubMed  Google Scholar 

  108. Plaitakis A (1990) Glutamate dysfunction and selective motor neuron degeneration in amyotrophic lateral sclerosis: a hypothesis. Ann Neurol 28:3–8

    CAS  PubMed  Google Scholar 

  109. Schutz B (2005) Imbalanced excitatory to inhibitory synaptic input precedes motor neuron degeneration in an animal model of amyotrophic lateral sclerosis. Neurobiol Dis 20:131–140

    PubMed  Google Scholar 

  110. Schiffer D, Cordera S, Giordana MT, Attanasio A, Pezzulo T (1995) Synaptic vesicle proteins, synaptophysin and chromogranin A in amyotrophic lateral sclerosis. J Neurol Sci 129(Suppl):68–74

    PubMed  Google Scholar 

  111. Cruz-Sanchez FF, Moral A, Rossi ML et al (1996) Synaptophysin in spinal anterior horn in aging and ALS: an immunohistological study. J Neural Transm 103:1317–1329

    CAS  PubMed  Google Scholar 

  112. Ikemoto A, Nakamura S, Akiguchi I, Hirano A (2002) Differential expression between synaptic vesicle proteins and presynaptic plasma membrane proteins in the anterior horn of amyotrophic lateral sclerosis. Acta Neuropathol 103:179–187

    CAS  PubMed  Google Scholar 

  113. Matsumoto S, Goto S, Kusaka H, Ito H, Imai T (1994) Synaptic pathology of spinal anterior horn cells in amyotrophic lateral sclerosis: an immunohistochemical study. J Neurol Sci 125:180–185

    CAS  PubMed  Google Scholar 

  114. Sasaki S, Maruyama S (1994) Decreased synaptophysin immunoreactivity of the anterior horns in motor neuron disease. Acta Neuropathol 87:125–128

    CAS  PubMed  Google Scholar 

  115. Nagao M, Misawa H, Kato S, Hirai S (1998) Loss of cholinergic synapses on the spinal motor neurons of amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 57:329–333

    CAS  PubMed  Google Scholar 

  116. Sasaki S, Iwata M (1996) Ultrastructural study of synapses in the anterior horn neurons of patients with amyotrophic lateral sclerosis. Neurosci Lett 204:53–56

    CAS  PubMed  Google Scholar 

  117. Sasaki S, Iwata M (1995) Synaptic loss in the proximal axon of anterior horn neurons in motor neuron disease. Acta Neuropathol 90:170–175

    CAS  PubMed  Google Scholar 

  118. Enterzari-Taher M, Eisen A, Stewart H, Nakajima M (1997) Abnormalities of cortical inhibitory neurons in amyotrophic lateral sclerosis. Muscle Nerve 20:65–71

    CAS  PubMed  Google Scholar 

  119. Lloyd CM, Richardson MP, Brooks DJ, Al-Chalabi A, Leigh PN (2000) Extramotor involvement in ALS: PET studies with the GABA(A) ligand [(11)C]flumazenil. Brain 123(Pt 11):2289–2296

    PubMed  Google Scholar 

  120. Petri S, Krampfl K, Hashemi F et al (2003) Distribution of GABAA receptor mRNA in the motor cortex of ALS patients. J Neuropathol Exp Neurol 62:1041–1051

    CAS  PubMed  Google Scholar 

  121. Miyazaki K, Nagai M, Morimoto N et al (2009) Spinal anterior horn has the capacity to self-regenerate in amyotrophic lateral sclerosis model mice. J Neurosci Res 87:3639–3648

    CAS  PubMed  Google Scholar 

  122. Zang DW, Lopes EC, Cheema SS (2005) Loss of synaptophysin-positive boutons on lumbar motor neurons innervating the medial gastrocnemius muscle of the SOD1G93A G1H transgenic mouse model of ALS. J Neurosci Res 79:694–699

    CAS  PubMed  Google Scholar 

  123. Fischer LR, Culver DG, Tennant P et al (2004) Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol 185:232–240

    PubMed  Google Scholar 

  124. Pullen AH, Athanasiou D (2009) Increase in presynaptic territory of C-terminals on lumbar motoneurons of G93A SOD1 mice during disease progression. Eur J Neurosci 29:551–561

    CAS  PubMed  Google Scholar 

  125. Chang Q, Martin LJ (2009) Glycinergic innervation of motoneurons is deficient in amyotrophic lateral sclerosis mice: a quantitative confocal analysis. Am J Pathol 174:574–585

    PubMed  Google Scholar 

  126. Chaudhry FA, Reimer RJ, Bellocchio EE et al (1998) The vesicular GABA transporter, VGAT, localizes to synaptic vesicles in sets of glycinergic as well as GABAergic neurons. J Neurosci 18:9733–9750

    CAS  PubMed  Google Scholar 

  127. Wootz H, Enjin A, Wallen-Mackenzie A, Lindholm D, Kullander K (2010) Reduced VGLUT2 expression increases motor neuron viability in Sod1(G93A) mice. Neurobiol Dis 37:58–66

    CAS  PubMed  Google Scholar 

  128. Stuehr DJ, Santolini J, Wang ZQ, Wei CC, Adak S (2004) Update on mechanism and catalytic regulation in the NO synthases. J Biol Chem 279:36167–36170

    CAS  PubMed  Google Scholar 

  129. Alderton WK, Cooper CE, Knowles RG (2001) Nitric oxide synthases: structure, function and inhibition. Biochem J 357:593–615

    CAS  PubMed  Google Scholar 

  130. Eliasson MJ, Blackshaw S, Schell MJ, Snyder SH (1997) Neuronal nitric oxide synthase alternatively spliced forms: prominent functional localizations in the brain. Proc Natl Acad Sci U S A 94:3396–3401

    CAS  PubMed  Google Scholar 

  131. Brenman JE, Chao DS, Gee SH et al (1996) Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and alpha1-syntrophin mediated by PDZ domains. Cell 84:757–767

    CAS  PubMed  Google Scholar 

  132. Garthwaite J, Charles SL, Chess-Williams R (1988) Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature 336:385–388

    CAS  PubMed  Google Scholar 

  133. Garthwaite J (2008) Concepts of neural nitric oxide-mediated transmission. Eur J Neurosci 27:2783–2802

    PubMed  Google Scholar 

  134. Hall CN, Garthwaite J (2009) What is the real physiological NO concentration in vivo? Nitric Oxide 21:92–103

    CAS  PubMed  Google Scholar 

  135. Malinski T, Bailey F, Zhang ZG, Chopp M (1993) Nitric oxide measured by a porphyrinic microsensor in rat brain after transient middle cerebral artery occlusion. J Cereb Blood Flow Metab 13:355–358

    CAS  PubMed  Google Scholar 

  136. Wu W (1993) Expression of nitric-oxide synthase (NOS) in injured CNS neurons as shown by NADPH diaphorase histochemistry. Exp Neurol 120:153–159

    CAS  PubMed  Google Scholar 

  137. Ruan RS, Leong SK, Yeoh KH (1994) Expression of NADPH-diaphorase activity in the facial motoneurons after compression of the facial nerve in the albino rat. Brain Res 652:350–352

    CAS  PubMed  Google Scholar 

  138. Ruan RS, Leong SK, Yeoh KH (1995) The role of nitric oxide in facial motoneuronal death. Brain Res 698:163–168

    CAS  PubMed  Google Scholar 

  139. Yu WH (1994) Nitric oxide synthase in motor neurons after axotomy. J Histochem Cytochem 42:451–457

    CAS  PubMed  Google Scholar 

  140. Yu WH (1997) Regulation of nitric oxide synthase expression in motoneurons following nerve injury. Dev Neurosci 19:247–254

    PubMed  Google Scholar 

  141. Chang HM, Ling EA, Lue JH, Wen CY, Shieh JY (2000) Melatonin attenuates neuronal NADPH-d/NOS expression in the hypoglossal nucleus of adult rats following peripheral nerve injury. Brain Res 873:243–251

    CAS  PubMed  Google Scholar 

  142. Chang HM, Lue JH, Wen CY, Shieh JY (2001) Axotomy along with hypoxia enhances the neuronal NADPH-d/NOS expression in lower brain stem motor neurons of adult rats. Exp Neurol 171:116–126

    CAS  PubMed  Google Scholar 

  143. Varathan V, Shigenaga Y, Takemura M (2001) Nitric oxide synthase/nicotinamide adenine dinucleotide phosphate-diaphorase in the brainstem trigeminal nuclei after transection of the masseteric nerve in rats. J Neurosci Res 66:428–438

    CAS  PubMed  Google Scholar 

  144. Wu W, Li L, Yick LW et al (2003) GDNF and BDNF alter the expression of neuronal NOS, c-Jun, and p75 and prevent motoneuron death following spinal root avulsion in adult rats. J Neurotrauma 20:603–612

    PubMed  Google Scholar 

  145. Martin LJ, Chen K, Liu Z (2005) Adult motor neuron apoptosis is mediated by nitric oxide and Fas death receptor linked by DNA damage and p53 activation. J Neurosci 25:6449–6459

    CAS  PubMed  Google Scholar 

  146. Gonzalez-Forero D, Portillo F, Gomez L, Montero F, Kasparov S, Moreno-Lopez B (2007) Inhibition of resting potassium conductances by long-term activation of the NO/cGMP/protein kinase G pathway: a new mechanism regulating neuronal excitability. J Neurosci 27:6302–6312

    CAS  PubMed  Google Scholar 

  147. Wei IH, Huang CC, Tseng CY et al (2008) Mild hypoxic preconditioning attenuates injury-induced NADPH-d/nNOS expression in brainstem motor neurons of adult rats. J Chem Neuroanat 35:123–132

    CAS  PubMed  Google Scholar 

  148. Zhou LH, Han S, Xie YY, Wang LL, Yao ZB (2008) Differences in c-jun and nNOS expression levels in motoneurons following different kinds of axonal injury in adult rats. Brain Cell Biol 36:213–227

    CAS  PubMed  Google Scholar 

  149. Rogerio F, Teixeira SA, Junior HJ et al (2006) mRNA and protein expression and activities of nitric oxide synthases in the lumbar spinal cord of neonatal rats after sciatic nerve transection and melatonin administration. Neurosci Lett 407:182–187

    CAS  PubMed  Google Scholar 

  150. Ferrante RJ, Shinobu LA, Schulz JB et al (1997) Increased 3-nitrotyrosine and oxidative damage in mice with a human copper/zinc superoxide dismutase mutation. Ann Neurol 42:326–334

    CAS  PubMed  Google Scholar 

  151. Shaw PJ, Ince PG, Falkous G, Mantle D (1995) Oxidative damage to protein in sporadic motor neuron disease spinal cord. Ann Neurol 38:691–695

    CAS  PubMed  Google Scholar 

  152. Beckman JS, Chen J, Crow JP, Ye YZ (1994) Reactions of nitric oxide, superoxide and peroxynitrite with superoxide dismutase in neurodegeneration. Prog Brain Res 103:371–380

    CAS  PubMed  Google Scholar 

  153. Tohgi H, Abe T, Yamazaki K, Murata T, Ishizaki E, Isobe C (1999) Increase in oxidized NO products and reduction in oxidized glutathione in cerebrospinal fluid from patients with sporadic form of amyotrophic lateral sclerosis. Neurosci Lett 260:204–206

    CAS  PubMed  Google Scholar 

  154. Boll MC, Alcaraz-Zubeldia M, Montes S, Rios C (2008) Free copper, ferroxidase and SOD1 activities, lipid peroxidation and NO(x) content in the CSF. A different marker profile in four neurodegenerative diseases. Neurochem Res 33:1717–1723

    CAS  PubMed  Google Scholar 

  155. Boll MC, Alcaraz-Zubeldia M, Montes S, Murillo-Bonilla L, Rios C (2003) Raised nitrate concentration and low SOD activity in the CSF of sporadic ALS patients. Neurochem Res 28:699–703

    CAS  PubMed  Google Scholar 

  156. Taskiran D, Sagduyu A, Yuceyar N, Kutay FZ, Pogun S (2000) Increased cerebrospinal fluid and serum nitrite and nitrate levels in amyotrophic lateral sclerosis. Int J Neurosci 101:65–72

    CAS  PubMed  Google Scholar 

  157. Babu GN, Kumar A, Chandra R, Puri SK, Kalita J, Misra UK (2008) Elevated inflammatory markers in a group of amyotrophic lateral sclerosis patients from northern India. Neurochem Res 33:1145–1149

    CAS  PubMed  Google Scholar 

  158. Isobe C, Abe T, Terayama Y (2010) Decrease in asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, in cerebrospinal fluid during elderly aging and in patients with sporadic form of amyotrophic lateral sclerosis. Neurosignals 18:43–48

    CAS  PubMed  Google Scholar 

  159. Kotani K, Ueno S, Sano A, Kakimoto Y (1992) Isolation and identification of methylarginines from bovine brain. J Neurochem 58:1127–1129

    CAS  PubMed  Google Scholar 

  160. Salter M, Duffy C, Garthwaite J, Strijbos PJ (1996) Ex vivo measurement of brain tissue nitrite and nitrate accurately reflects nitric oxide synthase activity in vivo. J Neurochem 66:1683–1690

    CAS  PubMed  Google Scholar 

  161. Phul RK, Smith ME, Shaw PJ, Ince PG (1998) Expression of nitric oxide synthase in the spinal cord in amyotrophic lateral sclerosis. J Neurol Sci 160(Suppl 1):S87–S91

    CAS  PubMed  Google Scholar 

  162. Phul RK, Shaw PJ, Ince PG, Smith ME (2000) Expression of nitric oxide synthase isoforms in spinal cord in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1:259–267

    CAS  PubMed  Google Scholar 

  163. Abe K, Pan LH, Watanabe M, Konno H, Kato T, Itoyama Y (1997) Upregulation of protein-tyrosine nitration in the anterior horn cells of amyotrophic lateral sclerosis. Neurol Res 19:124–128

    CAS  PubMed  Google Scholar 

  164. Sasaki S, Shibata N, Komori T, Iwata M (2000) iNOS and nitrotyrosine immunoreactivity in amyotrophic lateral sclerosis. Neurosci Lett 291:44–48

    CAS  PubMed  Google Scholar 

  165. Liu D, Bao F, Wen J, Liu J (2007) Mutation of superoxide dismutase elevates reactive species: comparison of nitration and oxidation of proteins in different brain regions of transgenic mice with amyotrophic lateral sclerosis. Neuroscience 146:255–264

    PubMed  Google Scholar 

  166. Chen K, Northington FJ, Martin LJ (2010) Inducible nitric oxide synthase is present in motor neuron mitochondria and Schwann cells and contributes to disease mechanisms in ALS mice. Brain Struct Funct 214:219–234

    CAS  PubMed  Google Scholar 

  167. Sasaki S, Warita H, Abe K, Iwata M (2002) Neuronal nitric oxide synthase (nNOS) immunoreactivity in the spinal cord of transgenic mice with G93A mutant SOD1 gene. Acta Neuropathol 103:421–427

    CAS  PubMed  Google Scholar 

  168. Sasaki S, Warita H, Abe K, Iwata M (2001) Inducible nitric oxide synthase (iNOS) and nitrotyrosine immunoreactivity in the spinal cords of transgenic mice with a G93A mutant SOD1 gene. J Neuropathol Exp Neurol 60:839–846

    CAS  PubMed  Google Scholar 

  169. Wengenack TM, Holasek SS, Montano CM, Gregor D, Curran GL, Poduslo JF (2004) Activation of programmed cell death markers in ventral horn motor neurons during early presymptomatic stages of amyotrophic lateral sclerosis in a transgenic mouse model. Brain Res 1027:73–86

    CAS  PubMed  Google Scholar 

  170. Almer G, Vukosavic S, Romero N, Przedborski S (1999) Inducible nitric oxide synthase up-regulation in a transgenic mouse model of familial amyotrophic lateral sclerosis. J Neurochem 72:2415–2425

    CAS  PubMed  Google Scholar 

  171. Lee J, Ryu H, Kowall NW (2009) Differential regulation of neuronal and inducible nitric oxide synthase (NOS) in the spinal cord of mutant SOD1 (G93A) ALS mice. Biochem Biophys Res Commun 387:202–206

    CAS  PubMed  Google Scholar 

  172. Cha CI, Kim JM, Shin DH et al (1998) Reactive astrocytes express nitric oxide synthase in the spinal cord of transgenic mice expressing a human Cu/Zn SOD mutation. Neuroreport 9:1503–1506

    CAS  PubMed  Google Scholar 

  173. Son M, Fathallah-Shaykh HM, Elliott JL (2001) Survival in a transgenic model of FALS is independent of iNOS expression. Ann Neurol 50:273

    CAS  PubMed  Google Scholar 

  174. Facchinetti F, Sasaki M, Cutting FB et al (1999) Lack of involvement of neuronal nitric oxide synthase in the pathogenesis of a transgenic mouse model of familial amyotrophic lateral sclerosis. Neuroscience 90:1483–1492

    CAS  PubMed  Google Scholar 

  175. Montero F, Sunico CR, Liu B, Paton JF, Kasparov S, Moreno-Lopez B (2010) Transgenic neuronal nitric oxide synthase expression induces axotomy-like changes in adult motoneurons. J Physiol 588:3425–3443

    CAS  PubMed  Google Scholar 

  176. Holstege G, Kuypers HG, Dekker JJ (1977) The organization of the bulbar fibre connections to the trigeminal, facial and hypoglossal motor nuclei. II. An autoradiographic tracing study in cat. Brain 100:264–286

    CAS  PubMed  Google Scholar 

  177. Borke RC, Nau ME, Ringler RL Jr (1983) Brain stem afferents of hypoglossal neurons in the rat. Brain Res 269:47–55

    CAS  PubMed  Google Scholar 

  178. Travers JB, Yoo JE, Chandran R, Herman K, Travers SP (2005) Neurotransmitter phenotypes of intermediate zone reticular formation projections to the motor trigeminal and hypoglossal nuclei in the rat. J Comp Neurol 488:28–47

    CAS  PubMed  Google Scholar 

  179. Singh OV, Yaster M, Xu JT et al (2009) Proteome of synaptosome-associated proteins in spinal cord dorsal horn after peripheral nerve injury. Proteomics 9:1241–1253

    CAS  PubMed  Google Scholar 

  180. Wang J, Irnaten M, Venkatesan P, Evans C, Baxi S, Mendelowitz D (2002) Synaptic activation of hypoglossal respiratory motorneurons during inspiration in rats. Neurosci Lett 332:195–199

    CAS  PubMed  Google Scholar 

  181. Vazquez C, Anesetti G, Martinez Palma L (1999) Transient expression of nitric oxide synthase in the hypoglossal nucleus of the rat during early postnatal development. Neurosci Lett 275:5–8

    CAS  PubMed  Google Scholar 

  182. Gao S, Cheng C, Zhao J et al (2008) Developmental regulation of PSD-95 and nNOS expression in lumbar spinal cord of rats. Neurochem Int 52:495–501

    CAS  PubMed  Google Scholar 

  183. Torrealba F, Muller C (1999) Ultrastructure of glutamate and GABA immunoreactive axon terminals of the rat nucleus tractus solitarius, with a note on infralimbic cortex afferents. Brain Res 820:20–30

    CAS  PubMed  Google Scholar 

  184. Yoshioka M, Tashiro Y, Inoue K, Kawai Y (2006) Postnatal development of GABAergic axon terminals in the rat nucleus of tractus solitarius. Brain Res 1107:111–120

    CAS  PubMed  Google Scholar 

  185. Wang S, Paton JF, Kasparov S (2007) Differential sensitivity of excitatory and inhibitory synaptic transmission to modulation by nitric oxide in rat nucleus tractus solitarii. Exp Physiol 92:371–382

    CAS  PubMed  Google Scholar 

  186. Bellamy TC, Griffiths C, Garthwaite J (2002) Differential sensitivity of guanylyl cyclase and mitochondrial respiration to nitric oxide measured using clamped concentrations. J Biol Chem 277:31801–31807

    CAS  PubMed  Google Scholar 

  187. Abudara V, Alvarez AF, Chase MH, Morales FR (2002) Nitric oxide as an anterograde neurotransmitter in the trigeminal motor pool. J Neurophysiol 88:497–506

    CAS  PubMed  Google Scholar 

  188. de Vente J, Asan E, Gambaryan S et al (2001) Localization of cGMP-dependent protein kinase type II in rat brain. Neuroscience 108:27–49

    PubMed  Google Scholar 

  189. Dontchev VD, Letourneau PC (2002) Nerve growth factor and semaphorin 3A signaling pathways interact in regulating sensory neuronal growth cone motility. J Neurosci 22:6659–6669

    CAS  PubMed  Google Scholar 

  190. Mann F, Miranda E, Weinl C, Harmer E, Holt CE (2003) B-type Eph receptors and ephrins induce growth cone collapse through distinct intracellular pathways. J Neurobiol 57:323–336

    CAS  PubMed  Google Scholar 

  191. Canossa M, Giordano E, Cappello S, Guarnieri C, Ferri S (2002) Nitric oxide down-regulates brain-derived neurotrophic factor secretion in cultured hippocampal neurons. Proc Natl Acad Sci U S A 99:3282–3287

    CAS  PubMed  Google Scholar 

  192. Ernst AF, Gallo G, Letourneau PC, McLoon SC (2000) Stabilization of growing retinal axons by the combined signaling of nitric oxide and brain-derived neurotrophic factor. J Neurosci 20:1458–1469

    CAS  PubMed  Google Scholar 

  193. Gallo G, Ernst AF, McLoon SC, Letourneau PC (2002) Transient PKA activity is required for initiation but not maintenance of BDNF-mediated protection from nitric oxide-induced growth-cone collapse. J Neurosci 22(12):5016–5023

    CAS  PubMed  Google Scholar 

  194. Ko GY, Kelly PT (1999) Nitric oxide acts as a postsynaptic signaling molecule in calcium/calmodulin-induced synaptic potentiation in hippocampal CA1 pyramidal neurons. J Neurosci 19:6784–6794

    CAS  PubMed  Google Scholar 

  195. Renteria RC, Constantine-Paton M (1996) Exogenous nitric oxide causes collapse of retinal ganglion cell axonal growth cones in vitro. J Neurobiol 29:415–428

    CAS  PubMed  Google Scholar 

  196. Hess DT, Patterson SI, Smith DS, Skene JH (1993) Neuronal growth cone collapse and inhibition of protein fatty acylation by nitric oxide. Nature 366:562–565

    CAS  PubMed  Google Scholar 

  197. Stroissnigg H, Trancikova A, Descovich L et al (2007) S-nitrosylation of microtubule-associated protein 1B mediates nitric-oxide-induced axon retraction. Nat Cell Biol 9:1035–1045

    CAS  PubMed  Google Scholar 

  198. Yamada RX, Matsuki N, Ikegaya Y (2006) Nitric oxide/cyclic guanosine monophosphate-mediated growth cone collapse of dentate granule cells. Neuroreport 17:661–665

    CAS  PubMed  Google Scholar 

  199. Gallo G, Letourneau PC (2004) Regulation of growth cone actin filaments by guidance cues. J Neurobiol 58:92–102

    CAS  PubMed  Google Scholar 

  200. Luo L (2002) Actin cytoskeleton regulation in neuronal morphogenesis and structural plasticity. Annu Rev Cell Dev Biol 18:601–635

    CAS  PubMed  Google Scholar 

  201. Sauzeau V, Rolli-Derkinderen M, Marionneau C, Loirand G, Pacaud P (2003) RhoA expression is controlled by nitric oxide through cGMP-dependent protein kinase activation. J Biol Chem 278:9472–9480

    CAS  PubMed  Google Scholar 

  202. Bivalacqua TJ, Liu T, Musicki B, Champion HC, Burnett AL (2007) Endothelial nitric oxide synthase keeps erection regulatory function balance in the penis. Eur Urol 51:1732–1740

    CAS  PubMed  Google Scholar 

  203. Soliman H, Craig GP, Nagareddy P et al (2008) Role of inducible nitric oxide synthase in induction of RhoA expression in hearts from diabetic rats. Cardiovasc Res 79:322–330

    CAS  PubMed  Google Scholar 

  204. Sauzeau V, Le Jeune H, Cario-Toumaniantz C et al (2000) Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitization of contraction in vascular smooth muscle. J Biol Chem 275:21722–21729

    CAS  PubMed  Google Scholar 

  205. Rolli-Derkinderen M, Sauzeau V, Boyer L et al (2005) Phosphorylation of serine 188 protects RhoA from ubiquitin/proteasome-mediated degradation in vascular smooth muscle cells. Circ Res 96:1152–1160

    CAS  PubMed  Google Scholar 

  206. Schmandke A, Strittmatter SM (2007) ROCK and Rho: biochemistry and neuronal functions of Rho-associated protein kinases. Neuroscientist 13(5):454–469

    CAS  PubMed  Google Scholar 

  207. Ridley AJ (2001) Rho family proteins: coordinating cell responses. Trends Cell Biol 11(12):471–477

    CAS  PubMed  Google Scholar 

  208. Schultess J, Danielewski O, Smolenski AP (2005) Rap1GAP2 is a new GTPase-activating protein of Rap1 expressed in human platelets. Blood 105(8):3185–3192

    CAS  PubMed  Google Scholar 

  209. Priviero FB, Jin LM, Ying Z, Teixeira CE, Webb RC (2010) Up-regulation of the RhoA/Rho-kinase signaling pathway in corpus cavernosum from endothelial nitric-oxide synthase (NOS), but not neuronal NOS, null mice. J Pharmacol Exp Ther 333(1):184–192

    CAS  PubMed  Google Scholar 

  210. John JP, Pintsov O, Petter-Puchner A et al (2007) Nitric oxide and oxygen radical attack on GDP-dissociation inhibitor 2 (GDI-2) in spinal cord injury of the rat. J Proteome Res 6:1500–1509

    CAS  PubMed  Google Scholar 

  211. Gallo G (2004) Myosin II activity is required for severing-induced axon retraction in vitro. Exp Neurol 189:112–121

    CAS  PubMed  Google Scholar 

  212. Svitkina TM, Verkhovsky AB, McQuade KM, Borisy GG (1997) Analysis of the actin-myosin II system in fish epidermal keratocytes: mechanism of cell body translocation. J Cell Biol 139:397–415

    CAS  PubMed  Google Scholar 

  213. Ramakers GJ (2002) Rho proteins, mental retardation and the cellular basis of cognition. Trends Neurosci 25:191–199

    CAS  PubMed  Google Scholar 

  214. Newey SE, Velamoor V, Govek EE, Van Aelst L (2005) Rho GTPases, dendritic structure, and mental retardation. J Neurobiol 64:58–74

    CAS  PubMed  Google Scholar 

  215. Gallo G, Yee HF Jr, Letourneau PC (2002) Actin turnover is required to prevent axon retraction driven by endogenous actomyosin contractility. J Cell Biol 158:1219–1228

    CAS  PubMed  Google Scholar 

  216. Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420:629–635

    CAS  PubMed  Google Scholar 

  217. Yue X, Dreyfus C, Kong TA, Zhou R (2008) A subset of signal transduction pathways is required for hippocampal growth cone collapse induced by ephrin-A5. Dev Neurobiol 68:1269–1286

    CAS  PubMed  Google Scholar 

  218. Hu JH, Chernoff K, Pelech S, Krieger C (2003) Protein kinase and protein phosphatase expression in the central nervous system of G93A mSOD over-expressing mice. J Neurochem 85:422–431

    CAS  PubMed  Google Scholar 

  219. Wood PL, Emmett MR, Rao TS, Cler J, Mick S, Iyengar S (1990) Inhibition of nitric oxide synthase blocks N-methyl-D-aspartate-, quisqualate-, kainate-, harmaline-, and pentylenetetrazole-dependent increases in cerebellar cyclic GMP in vivo. J Neurochem 55:346–348

    CAS  PubMed  Google Scholar 

  220. Garcia Del Cano G, Gerrikagoitia I, Sarasa M, Matute C, Martinez-Millan L (2000) Ionotropic glutamate receptor subunits are differentially regulated in the motoneuronal pools of the rat hypoglossal nucleus in response to axotomy. J Neurocytol 29:509–523

    CAS  PubMed  Google Scholar 

  221. Huh GS, Boulanger LM, Du H, Riquelme PA, Brotz TM, Shatz CJ (2000) Functional requirement for class I MHC in CNS development and plasticity. Science 290:2155–2159

    CAS  PubMed  Google Scholar 

  222. Emirandetti A, Simoes GF, Zanon RG, Oliveira AL (2010) Spinal motoneuron synaptic plasticity after axotomy in the absence of inducible nitric oxide synthase. J Neuroinflammation 7:31

    PubMed  Google Scholar 

  223. Mallory M, Honer W, Hsu L, Johnson R, Rockenstein E, Masliah E (1999) In vitro synaptotrophic effects of cerebrolysin in NT2N cells. Acta Neuropathol 97:437–446

    CAS  PubMed  Google Scholar 

  224. Ruther E, Ritter R, Apecechea M, Freytag S, Gmeinbauer R, Windisch M (2000) Sustained improvements in patients with dementia of Alzheimer's type (DAT) 6 months after termination of cerebrolysin therapy. J Neural Transm 107:815–829

    CAS  PubMed  Google Scholar 

  225. Furuyama T, Inagaki S, Takagi H (1993) Localizations of alpha 1 and beta 1 subunits of soluble guanylate cyclase in the rat brain. Brain Res Mol Brain Res 20:335–344

    CAS  PubMed  Google Scholar 

  226. Tsukuda K, Mogi M, Iwanami J et al (2009) Cognitive deficit in amyloid-beta-injected mice was improved by pretreatment with a low dose of telmisartan partly because of peroxisome proliferator-activated receptor-gamma activation. Hypertension 54:782–787

    CAS  PubMed  Google Scholar 

  227. Medeiros R, Prediger RD, Passos GF et al (2007) Connecting TNF-alpha signaling pathways to iNOS expression in a mouse model of Alzheimer's disease: relevance for the behavioral and synaptic deficits induced by amyloid beta protein. J Neurosci 27:5394–5404

    CAS  PubMed  Google Scholar 

  228. de la Torre JC, Pappas BA, Prevot V et al (2003) Hippocampal nitric oxide upregulation precedes memory loss and A beta 1-40 accumulation after chronic brain hypoperfusion in rats. Neurol Res 25:635–641

    PubMed  Google Scholar 

  229. Hantraye P, Brouillet E, Ferrante R et al (1996) Inhibition of neuronal nitric oxide synthase prevents MPTP-induced parkinsonism in baboons. Nat Med 2:1017–1021

    CAS  PubMed  Google Scholar 

  230. Haik KL, Shear DA, Hargrove C et al (2008) 7-Nitroindazole attenuates 6-hydroxydopamine-induced spatial learning deficits and dopamine neuron loss in a presymptomatic animal model of Parkinson's disease. Exp Clin Psychopharmacol 16:178–189

    CAS  PubMed  Google Scholar 

  231. Li Y, Kustova Y, Sei Y, Basile AS (1997) Regional changes in constitutive, but not inducible NOS expression in the brains of mice infected with the LP-BM5 leukemia virus. Brain Res 752:107–116

    CAS  PubMed  Google Scholar 

  232. Komulainen P, Pedersen M, Hanninen T et al (2008) BDNF is a novel marker of cognitive function in ageing women: the DR's EXTRA study. Neurobiol Learn Mem 90:596–603

    CAS  PubMed  Google Scholar 

  233. Siegel GJ, Chauhan NB (2000) Neurotrophic factors in Alzheimer's and Parkinson's disease brain. Brain Res Brain Res Rev 33:199–227

    CAS  PubMed  Google Scholar 

  234. Ferrer I, Goutan E, Marin C, Rey MJ, Ribalta T (2000) Brain-derived neurotrophic factor in Huntington disease. Brain Res 866:257–261

    CAS  PubMed  Google Scholar 

  235. Boven LA, Middel J, Portegies P, Verhoef J, Jansen GH, Nottet HS (1999) Overexpression of nerve growth factor and basic fibroblast growth factor in AIDS dementia complex. J Neuroimmunol 97:154–162

    CAS  PubMed  Google Scholar 

  236. Simmons DA, Rex CS, Palmer L et al (2009) Up-regulating BDNF with an ampakine rescues synaptic plasticity and memory in Huntington's disease knockin mice. Proc Natl Acad Sci U S A 106:4906–4911

    CAS  PubMed  Google Scholar 

  237. Giralt A, Rodrigo T, Martin ED et al (2009) Brain-derived neurotrophic factor modulates the severity of cognitive alterations induced by mutant huntingtin: involvement of phospholipaseCgamma activity and glutamate receptor expression. Neuroscience 158:1234–1250

    CAS  PubMed  Google Scholar 

  238. Patanella AK, Zinno M, Quaranta D et al (2010) Correlations between peripheral blood mononuclear cell production of BDNF, TNF-alpha, IL-6, IL-10 and cognitive performances in multiple sclerosis patients. J Neurosci Res 88:1106–1112

    CAS  PubMed  Google Scholar 

  239. Heredia L, Helguera P, de Olmos S et al (2006) Phosphorylation of actin-depolymerizing factor/cofilin by LIM-kinase mediates amyloid beta-induced degeneration: a potential mechanism of neuronal dystrophy in Alzheimer's disease. J Neurosci 26:6533–6542

    CAS  PubMed  Google Scholar 

  240. Petratos S, Li QX, George AJ et al (2008) The beta-amyloid protein of Alzheimer's disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanism. Brain 131:90–108

    PubMed  Google Scholar 

  241. Huesa G, Baltrons MA, Gomez-Ramos P et al (2010) Altered distribution of RhoA in Alzheimer's disease and AbetaPP overexpressing mice. J Alzheimers Dis 19:37–56

    PubMed  Google Scholar 

  242. Li M, Huang Y, Ma AA, Lin E, Diamond MI (2009) Y-27632 improves rotarod performance and reduces huntingtin levels in R6/2 mice. Neurobiol Dis 36:413–420

    CAS  PubMed  Google Scholar 

  243. Zhang Z, Schittenhelm J, Meyermann R, Schluesener HJ (2008) Lesional accumulation of RhoA(+) cells in brains of experimental autoimmune encephalomyelitis and multiple sclerosis. Neuropathol Appl Neurobiol 34:231–240

    CAS  PubMed  Google Scholar 

  244. Yu JZ, Ding J, Ma CG et al (2010) Therapeutic potential of experimental autoimmune encephalomyelitis by Fasudil, a Rho kinase inhibitor. J Neurosci Res 88:1664–1672

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from the Ministerio de Ciencia e Innovación, (SAF2008-01415) and the Consejería de Innovación, Ciencia y Empresa from the Junta de Andalucía (PAI2007-CTS-02606), both co-financed with FEDER funds and the Mútua Madrileña Foundation, Spain. We thank Elaine Lilly, Ph.D. (Writer’s First Aid), for English language revision of this manuscript.

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  1. Grupo de NeuroDegeneración y NeuroReparación (GRUNEDERE), Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Plaza Falla, 9, 11003, Cádiz, Spain

    Bernardo Moreno-López, Carmen R. Sunico & David González-Forero

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Moreno-López, B., Sunico, C.R. & González-Forero, D. NO Orchestrates the Loss of Synaptic Boutons from Adult “Sick” Motoneurons: Modeling a Molecular Mechanism. Mol Neurobiol 43, 41–66 (2011). https://doi.org/10.1007/s12035-010-8159-8

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  • DOI: https://doi.org/10.1007/s12035-010-8159-8

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