Neurotrophic factor expression in denervated motor and sensory Schwann cells: Relevance to specificity of peripheral nerve regeneration

Experimental Neurology

Volumn 254, Issue , 2014, Pages 99-108

  Gordon, Tessa ^a  

^a HOSPITAL FOR SICK CHILDREN   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ANIMALS; AXONS; FEMALE; PERIPHERAL NERVOUS SYSTEM DISEASES; SCHWANN CELLS;

EID: 84893603609     PISSN: 00144886     EISSN: 10902430     Source Type: Journal    
DOI: 10.1016/j.expneurol.2014.01.012     Document Type: Note

References (114)

1. Almad A., Sahinkaya F.R., McTigue D.M. Oligodendrocyte fate after spinal cord injury. Neurotherapeutics 2011, 8:262-273.
2. Al-Majed A.A., Brushart T.M., Gordon T. Electrical stimulation accelerates and increases expression of BDNF and trkB mRNA in regenerating rat femoral motoneurons. Eur. J. Neurosci. 2000, 12:4381-4390.
3. Al-Majed A.A., Neumann C.M., Brushart T.M., Gordon T. Brief electrical stimulation promotes the speed and accuracy of motor axonal regeneration. J. Neurosci. 2000, 20:2602-2608.
4. Arthur-Farraj P., Wanek K., Hantke J., Davis C.M., Jayakar A., Parkinson D.B., Mirsky R., Jessen K.R. Mouse Schwann cells need both NRG1 and cyclic AMP to myelinate. GLIA 2011, 59:720-733.
5. Arthur-Farraj P.J., Latouche M., Wilton D.K., Quintes S., Chabrol E., Banerjee A., Woodhoo A., Jenkins B., Rahman M., Turmaine M., Wicher G.K., Mitter R., Greensmith L., Behrens A., Raivich G., Mirsky R., Jessen K.R. c-Jun reprograms Schwann cells of injured nerves to generate a repair cell essential for regeneration. Neuron 2012, 75:633-647.
6. Avellino A.M., Dailey A.T., Harlan J.M., Sharar S.R., Winn R.K., McNutt L.D., Kliot M. Blocking of up-regulated ICAM-1 does not prevent macrophage infiltration during Wallerian degeneration of peripheral nerve. Exp. Neurol. 2004, 187:430-444.
7. Barres B.A., Barde Y. Neuronal and glial cell biology. Curr. Opin. Neurobiol. 2000, 10:642-648.
8. Berry M., Ibrahim M., Carlile J., Ruge F., Duncan A., Butt A.M. Axon-glial relationships in the anterior medullary velum of the adult rat. J. Neurocytol. 1995, 24:965-983.
9. Bibel M., Barde Y.A. Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system. Genes Dev 2000, 14:2919-2937.
10. Birchmeier C. ErbB receptors and the development of the nervous system. Exp. Cell Res. 2009, 315:611-618.
11. Birchmeier C., Nave K.A. Neuregulin-1, a key axonal signal that drives Schwann cell growth and differentiation. GLIA 2008, 56:1491-1497.
12. Blakemore W.F., Keirstead H.S. The origin of remyelinating cells in the central nervous system. J. Neuroimmunol. 1999, 98:69-76.
13. Boyd J.G., Gordon T. Neurotrophic factors and their receptors in axonal regeneration and functional recovery after peripheral nerve injury. Mol. Neurobiol. 2003, 27:277-324.
14. Britsch S., Goerich D.E., Riethmacher D., Peirano R.I., Rossner M., Nave K.A., Birchmeier C., Wegner M. The transcription factor Sox10 is a key regulator of peripheral glial development. Genes Dev. 2001, 15:66-78.
15. Brushart T.M. Preferential reinnervation of motor nerves by regenerating motor axons. J. Neurosci. 1988, 8:1026-1031.
16. Brushart T.M. Motor axons preferentially reinnervate motor pathways. J. Neurosci. 1993, 13:2730-2738.
17. Brushart T.M. Nerve Repair 2011, Oxford University Press, USA.
18. Brushart T.M., Hoffman P.N., Royall R.M., Murinson B.B., Witzel C., Gordon T. Electrical stimulation promotes motoneuron regeneration without increasing its speed or conditioning the neuron. J. Neurosci. 2002, 22:6631-6638.
19. Brushart T.M., Jari R., Verge V., Rohde C., Gordon T. Electrical stimulation restores the specificity of sensory axon regeneration. Exp. Neurol. 2005, 194:221-229.
20. Brushart T.M., Aspalter M., Griffin J.W., Redett R., Hameed H., Zhou C., Wright M., Vyas A., Hoke A. Schwann cell phenotype is regulated by axon modality and central-peripheral location, and persists in vitro. Exp. Neurol. 2013, 247:272-281.
21. Bunge M.B., Bunge R.P., PAPPAS G.D. Electron microscopic demonstration of connections between glia and myelin sheaths in the developing mammalian central nervous system. J. Cell Biol. 1962, 12:448-453.
22. Buttermore E.D., Thaxton C.L., Bhat M.A. Organization and maintenance of molecular domains in myelinated axons. J. Neurosci. Res. 2013, 91:603-622.
23. Chen Y.Y., McDonald D., Cheng C., Magnowski B., Durand J., Zochodne D.W. Axon and Schwann cell partnership during nerve regrowth. J. Neuropathol. Exp. Neurol. 2005, 64:613-622.
24. Coleman M. Axon degeneration mechanisms: commonality amid diversity. Nat. Rev. Neurosci. 2005, 6:889-898.
25. Crawford A.T., Desai D., Gokina P., Basak S., Kim H.A. E-cadherin expression in postnatal Schwann cells is regulated by the cAMP-dependent protein kinase a pathway. GLIA 2008, 56:1637-1647.
26. De F.C., Hunt S.P. The differential control of c-jun expression in regenerating sensory neurons and their associated glial cells. J. Neurosci. 1994, 14:2911-2923.
27. Devor M., Govrin-Lippmann R. Maturation of axonal sprouts after nerve crush. Exp. Neurol. 1979, 64:260-270.
28. Dong Z., Brennan A., Liu N., Yarden Y., Lefkowitz G., Mirsky R., Jessen K.R. Neu differentiation factor is a neuron-glia signal and regulates survival, proliferation, and maturation of rat Schwann cell precursors. Neuron 1995, 15:585-596.
29. Eberhardt K.A., Irintchev A., Al-Majed A.A., Simova O., Brushart T.M., Gordon T., Schachner M. BDNF/TrkB signaling regulates HNK-1 carbohydrate expression in regenerating motor nerves and promotes functional recovery after peripheral nerve repair. Exp. Neurol. 2006, 198:500-510.
30. Falls D.L. Neuregulins and the neuromuscular system: 10years of answers and questions. J. Neurocytol. 2003, 32:619-647.
31. Feltri M.L., Graus P.D., Previtali S.C., Nodari A., Migliavacca B., Cassetti A., Littlewood-Evans A., Reichardt L.F., Messing A., Quattrini A., Mueller U., Wrabetz L. Conditional disruption of beta 1 integrin in Schwann cells impedes interactions with axons. J. Cell Biol. 2002, 156:199-209.
32. Fenrich K., Gordon T. Canadian Association of Neuroscience review: axonal regeneration in the peripheral and central nervous systems-current issues and advances. Can. J. Neurol. Sci. 2004, 31:142-156.
33. Franz C.K., Rutishauser U., Rafuse V.F. Intrinsic neuronal properties control selective targeting of regenerating motoneurons. Brain 2008, 131:1492-1505.
34. Fu S.Y., Gordon T. The cellular and molecular basis of peripheral nerve regeneration. Mol. Neurobiol. 1997, 14:67-116.
35. Funakoshi H., Frisen J., Barbany G., Timmusk T., Zachrisson O., Verge V.M., Persson H. Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve. J. Cell Biol. 1993, 123:455-465.
36. Garratt A.N., Britsch S., Birchmeier C. Neuregulin, a factor with many functions in the life of a Schwann cell. Bioessays 2000, 22:987-996.
37. Gaudet A.D., Popovich P.G., Ramer M.S. Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. J. Neuroinflammation 2011, 8:110.
38. Georgiou J., Robitaille R., Charlton M.P. Muscarinic control of cytoskeleton in perisynaptic glia. J. Neurosci. 1999, 19:3836-3846.
39. Geremia N.M., Gordon T., Brushart T.M., Al-Majed A.A., Verge V.M. Electrical stimulation promotes sensory neuron regeneration and growth-associated gene expression. Exp. Neurol. 2007, 205:347-359.
40. Gordon T. Dependence of peripheral nerves on their target organs. Somatic and Autonomic Nerve-Muscle Interactions 1983, 289-316. Elsevier, Amsterdam. G. Burnstock, R. O'Brien, G. Vrbova (Eds.).
41. Gordon T. The role of neurotrophic factors in nerve regeneration. Neurosurg. Focus 2009, 26(E3):1-10.
42. Gordon T., Udina E., Verge V.M., de Chaves E.I. Brief electrical stimulation accelerates axon regeneration in the peripheral nervous system and promotes sensory axon regeneration in the central nervous system. Motor Control 2009, 13:412-441.
43. Grafstein B. The nerve cell body response to axotomy. Exp. Neurol. 1975, 48:32-51.
44. Grafstein B., McQuarrie I.G. Role of the nerve cell body in axonal regeneration. Neuronal Plasticity 1978, 155-196. Raven, New York. C.W. Cotman (Ed.).
45. Griffin J.W., Thompson W.J. Biology and pathology of nonmyelinating Schwann cells. GLIA 2008, 56:1518-1531.
46. Gruber H., Zenker W. Acetylcholinesterase: histochemical differentiation between motor and sensory nerve fibres. Brain Res. 1973, 51:207-214.
47. Haftek J., Thomas P.K. Electron-microscope observations on the effects of localized crush injuries on the connective tissues of peripheral nerve. J. Anat. 1968, 103:233-243.
48. Hall S.M. The effect of inhibiting Schwann cell mitosis on the re-innervation of acellular autografts in the peripheral nervous system of the mouse. Neuropathol. Appl. Neurobiol. 1986, 12:401-414.
49. Herdegen T., Gass P., Brecht S., Neiss W.F., Schmid W. The transcription factor CREB is not phosphorylated at serine 133 in axotomized neurons: implications for the expression of AP-1 proteins. Brain Res. Mol. Brain Res. 1994, 26:259-270.
50. Heumann R., Korsching S., Bandtlow C., Thoenen H. Changes of nerve growth factor synthesis in nonneuronal cells in response to sciatic nerve transection. J. Cell Biol. 1987, 104:1623-1631.
51. Heumann R., Lindholm D., Bandtlow C., Meyer M., Radeke M.J., Misko T.P., Shooter E., Thoenen H. Differential regulation of mRNA encoding nerve growth factor and its receptor in rat sciatic nerve during development, degeneration, and regeneration: role of macrophages. Proc. Natl. Acad. Sci. U. S. A. 1987, 84:8735-8739.
52. Hildebrand C., Remahl S., Persson H., Bjartmar C. Myelinated nerve fibres in the CNS. Prog. Neurobiol. 1993, 40:319-384.
53. Hirano A., Levine S., Zimmerman H.M. Remyelination in the central nervous system after cyanide intoxication. J. Neuropathol. Exp. Neurol. 1968, 27:234-245.
54. Hoke A., Redett R., Hameed H., Jari R., Zhou C., Li Z.B., Griffin J.W., Brushart T.M. Schwann cells express motor and sensory phenotypes that regulate axon regeneration. J. Neurosci. 2006, 26:9646-9655.
55. Huang J., Ye Z., Hu X., Lu L., Luo Z. Electrical stimulation induces calcium-dependent release of NGF from cultured Schwann cells. GLIA 2010, 58:622-631.
56. Huxley A.F., Stampfli R. Evidence for saltatory conduction in peripheral myelinated nerve fibres. J. Physiol. 1949, 108:315-339.
57. Ibrahim M., Butt A.M., Berry M. Relationship between myelin sheath diameter and internodal length in axons of the anterior medullary velum of the adult rat. J. Neurol. Sci. 1995, 133:119-127.
58. Jahromi B.S., Robitaille R., Charlton M.P. Transmitter release increases intracellular calcium in perisynaptic Schwann cells in situ. Neuron 1992, 8:1069-1077.
59. Jenkins R., Hunt S.P. Long-term increase in the levels of c-jun mRNA and jun protein-like immunoreactivity in motor and sensory neurons following axon damage. Neurosci. Lett. 1991, 129:107-110.
60. Jessen K.R., Mirsky R. The origin and development of glial cells in peripheral nerves. Nat. Rev. Neurosci. 2005, 6:671-682.
61. Jessen K.R., Mirsky R. Negative regulation of myelination: relevance for development, injury, and demyelinating disease. GLIA 2008, 56:1552-1565.
62. Jin K., Zhu Y., Sun Y., Mao X.O., Xie L., Greenberg D.A. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc. Natl. Acad. Sci. U. S. A. 2002, 99:11946-11950.
63. Klimaschewski L., Hausott B., Angelov D.N. The pros and cons of growth factors and cytokines in peripheral axon regeneration. Int. Rev. Neurobiol. 2013, 108:137-171.
64. Knusel B., Michel P.P., Schwaber J.S., Hefti F. Selective and nonselective stimulation of central cholinergic and dopaminergic development in vitro by nerve growth factor, basic fibroblast growth factor, epidermal growth factor, insulin and the insulin-like growth factors I and II. J. Neurosci. 1990, 10:558-570.
65. Lieberman A.R. The axon reaction: a review of the principal features of perikaryal responses to axon injury. Int. Rev. Neurobiol. 1971, 14:49-124.
66. Lubinska L. Early course of Wallerian degeneration in myelinated fibres of the rat phrenic nerve. Brain Res. 1977, 130:47-63.
67. Martini R., Schachner M. Immunoelectron microscopic localization of neural cell adhesion molecule (L1, N-CAM, and myelin-associated glycoprotein) in regenerating adult mouse sciatic nerve. J. Cell Biol. 1988, 106:1735-1746.
68. Martini R., Schachner M., Brushart T.M. The L2/HNK-1 carbohydrate is preferentially expressed by previously motor axon-associated Schwann cells in reinnervated peripheral nerves. J. Neurosci. 1994, 14:7180-7191.
69. Mears S., Schachner M., Brushart T.M. Antibodies to myelin-associated glycoprotein accelerate preferential motor reinnervation. J. Peripher. Nerv. Syst. 2003, 8:91-99.
70. Meyer M., Matsuoka I., Wetmore C., Olson L., Thoenen H. Enhanced synthesis of brain-derived neurotrophic factor in the lesioned peripheral nerve: different mechanisms are responsible for the regulation of BDNF and NGF mRNA. J. Cell Biol. 1992, 119:45-54.
71. Mi R., Chen W., Hoke A. Pleiotrophin is a neurotrophic factor for spinal motor neurons. Proc. Natl. Acad. Sci. U. S. A. 2007, 104:4664-4669.
72. Michailov G.V., Sereda M.W., Brinkmann B.G., Fischer T.M., Haug B., Birchmeier C., Role L., Lai C., Schwab M.H., Nave K.A. Axonal neuregulin-1 regulates myelin sheath thickness. Science 2004, 304:700-703.
73. Mirsky R., Woodhoo A., Parkinson D.B., Arthur-Farraj P., Bhaskaran A., Jessen K.R. Novel signals controlling embryonic Schwann cell development, myelination and dedifferentiation. J. Peripher. Nerv. Syst. 2008, 13:122-135.
74. Morrissey T.K., Levi A.D., Nuijens A., Sliwkowski M.X., Bunge R.P. Axon-induced mitogenesis of human Schwann cells involves heregulin and p185erbB2. Proc. Natl. Acad. Sci. U. S. A. 1995, 92:1431-1435.
75. Neufeld G., Cohen T., Gengrinovitch S., Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 1999, 13:9-22.
76. Paratore C., Goerich D.E., Suter U., Wegner M., Sommer L. Survival and glial fate acquisition of neural crest cells are regulated by an interplay between the transcription factor Sox10 and extrinsic combinatorial signaling. Development 2001, 128:3949-3961.
77. Parkinson D.B., Dickinson S., Bhaskaran A., Kinsella M.T., Brophy P.J., Sherman D.L., Sharghi-Namini S., Duran Alonso M.B., Mirsky R., Jessen K.R. Regulation of the myelin gene periaxin provides evidence for Krox-20-independent myelin-related signalling in Schwann cells. Mol. Cell. Neurosci. 2003, 23:13-27.
78. Parkinson D.B., Bhaskaran A., Droggiti A., Dickinson S., D'Antonio M., Mirsky R., Jessen K.R. Krox-20 inhibits Jun-NH2-terminal kinase/c-Jun to control Schwann cell proliferation and death. J. Cell Biol. 2004, 164:385-394.
79. Parkinson D.B., Bhaskaran A., Arthur-Farraj P., Noon L.A., Woodhoo A., Lloyd A.C., Feltri M.L., Wrabetz L., Behrens A., Mirsky R., Jessen K.R. c-Jun is a negative regulator of myelination. J. Cell Biol. 2008, 181:625-637.
80. Pellegrino R.G., Spencer P.S. Schwann cell mitosis in response to regenerating peripheral axons in vivo. Brain Res. 1985, 341:16-25.
81. Peng H.B., Ali A.A., Dai Z., Daggett D.F., Raulo E., Rauvala H. The role of heparin-binding growth-associated molecule (HB-GAM) in the postsynaptic induction in cultured muscle cells. J. Neurosci. 1995, 15:3027-3038.
82. Pereira J.A., Lebrun-Julien F., Suter U. Molecular mechanisms regulating myelination in the peripheral nervous system. Trends Neurosci. 2012, 35:123-134.
83. Pfister B.J., Gordon T., Loverde J.R., Kochar A.S., Mackinnon S.E., Cullen D.K. Biomedical engineering strategies for peripheral nerve repair: surgical applications, state of the art, and future challenges. Crit. Rev. Biomed. Eng. 2011, 39:81-124.
84. Rotshenker S. Wallerian degeneration: the innate-immune response to traumatic nerve injury. J. Neuroinflammation 2011, 8:109.
85. Salzer J.L. Axonal regulation of Schwann cell ensheathment and myelination. J. Peripher. Nerv. Syst. 2012, 17(Suppl. 3):14-19.
86. Salzer J.L., Brophy P.J., Peles E. Molecular domains of myelinated axons in the peripheral nervous system. GLIA 2008, 56:1532-1540.
87. Schachner M. Functional implications of glial cell recognition molecules. Semin. Neurosci. 1990, 2:497-507.
88. Schubert T., Friede R.L. The role of endoneurial fibroblasts in myelin degradation. J. Neuropathol. Exp. Neurol. 1981, 40:134-154.
89. Shah N.M., Marchionni M.A., Isaacs I., Stroobant P., Anderson D.J. Glial growth factor restricts mammalian neural crest stem cells to a glial fate. Cell 1994, 77:349-360.
90. Shy M.E., Shi Y., Wrabetz L., Kamholz J., Scherer S.S. Axon-Schwann cell interactions regulate the expression of c-jun in Schwann cells. J. Neurosci. Res. 1996, 43:511-525.
91. Son Y.J., Thompson W.J. Schwann cell processes guide regeneration of peripheral axons. Neuron 1995, 14:125-132.
92. Son Y.J., Trachtenberg J.T., Thompson W.J. Schwann cells induce and guide sprouting and reinnervation of neuromuscular junctions. Trends Neurosci. 1996, 19:280-285.
93. Stoll G., Muller H.W. Nerve injury, axonal degeneration and neural regeneration: basic insights. Brain Pathol. 1999, 9:313-325.
94. Stoll G., Griffin J.W., Li C.Y., Trapp B.D. Wallerian degeneration in the peripheral nervous system: participation of both Schwann cells and macrophages in myelin degradation. J. Neurocytol. 1989, 18:671-683.
95. Szynkaruk M., Kemp S.W., Wood M.D., Gordon T., Borschel G.H. Experimental and clinical evidence for use of decellularized nerve allografts in peripheral nerve gap reconstruction. Tissue Eng. Part B Rev. 2013, 19:83-96.
96. Taveggia C., Zanazzi G., Petrylak A., Yano H., Rosenbluth J., Einheber S., Xu X., Esper R.M., Loeb J.A., Shrager P., Chao M.V., Falls D.L., Role L., Salzer J.L. Neuregulin-1 type III determines the ensheathment fate of axons. Neuron 2005, 47:681-694.
97. Thaxton C., Bhat M.A. Myelination and regional domain differentiation of the axon. Results Probl. Cell Differ. 2009, 48:1-28.
98. Titmus M.J., Faber D.S. Axotomy-induced alterations in the electrophysiological characteristics of neurons. Prog. Neurobiol. 1990, 35:1-51.
99. Topilko P., Schneider-Maunoury S., Levi G., Baron-Van E.A., Chennoufi A.B., Seitanidou T., Babinet C., Charnay P. Krox-20 controls myelination in the peripheral nervous system. Nature 1994, 371:796-799.
100. Tucker K.L., Meyer M., Barde Y.A. Neurotrophins are required for nerve growth during development. Nat. Neurosci. 2001, 4:29-37.
101. Verge V.M., Gratto K.A., Karchewski L.A., Richardson P.M. Neurotrophins and nerve injury in the adult. Philos. Trans. R. Soc. Lond. B Biol. Sci. 1996, 351:423-430.
102. Vrbova G., Mehra N., Shanmuganathan H., Tyreman N., Schachner M., Gordon T. Chemical communication between regenerating motor axons and Schwann cells in the growth pathway. Eur. J. Neurosci. 2009, 30:366-375.
103. Vyas A., Li Z., Aspalter M., Feiner J., Hoke A., Zhou C., O'Daly A., Abdullah M., Rohde C., Brushart T.M. An in vitro model of adult mammalian nerve repair. Exp. Neurol. 2010, 223:112-118.
104. Wan L.D., Xia R., Ding W.L. Electrical stimulation enhanced remyelination of injured sciatic nerves by increasing neurotrophins. Neurosciences 2010, 169:1029-1038.
105. Wang J.Y., Miller S.J., Falls D.L. The N-terminal region of neuregulin isoforms determines the accumulation of cell surface and released neuregulin ectodomain. J. Biol. Chem. 2001, 276:2841-2851.
106. Waxman S.G., Bennett M.V. Relative conduction velocities of small myelinated and non-myelinated fibres in the central nervous system. Nat. New Biol. 1972, 238:217-219.
107. Winseck A.K., Oppenheim R.W. An in vivo analysis of Schwann cell programmed cell death in embryonic mice: the role of axons, glial growth factor, and the pro-apoptotic gene Bax. Eur. J. Neurosci. 2006, 24:2105-2117.
108. Winseck A.K., Caldero J., Ciutat D., Prevette D., Scott S.A., Wang G., Esquerda J.E., Oppenheim R.W. In vivo analysis of Schwann cell programmed cell death in the embryonic chick: regulation by axons and glial growth factor. J. Neurosci. 2002, 22:4509-4521.
109. Witzel C., Rohde C., Brushart T.M. Pathway sampling by regenerating peripheral axons. J. Comp. Neurol. 2005, 485:183-190.
110. Wolpowitz D., Mason T.B., Dietrich P., Mendelsohn M., Talmage D.A., Role L.W. Cysteine-rich domain isoforms of the neuregulin-1 gene are required for maintenance of peripheral synapses. Neuron 2000, 25:79-91.
111. Woodhoo A., Alonso M.B., Droggiti A., Turmaine M., D'Antonio M., Parkinson D.B., Wilton D.K., Al-Shawi R., Simons P., Shen J., Guillemot F., Radtke F., Meijer D., Feltri M.L., Wrabetz L., Mirsky R., Jessen K.R. Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity. Nat. Neurosci. 2009, 12:839-847.
112. Zhang Y., Bekku Y., Dzhashiashvili Y., Armenti S., Meng X., Sasaki Y., Milbrandt J., Salzer J.L. Assembly and maintenance of nodes of Ranvier rely on distinct sources of proteins and targeting mechanisms. Neuron 2012, 73:92-107.
113. Zigmond R.E. gp130 Cytokines are positive signals triggering changes in gene expression and axon outgrowth in peripheral neurons following injury. Front. Mol. Neurosci. 2011, 4:62.
114. Zigmond R.E. Cytokines that promote nerve regeneration. Exp. Neurol. 2012, 238:101-106.