Skip to main content
Top
Published in: Molecular Pain 1/2009

Open Access 01-12-2009 | Research

Plasticity in expression of the glutamate transporters GLT-1 and GLAST in spinal dorsal horn glial cells following partial sciatic nerve ligation

Authors: Wen-Jun Xin, Han-Rong Weng, Patrick M Dougherty

Published in: Molecular Pain | Issue 1/2009

Login to get access

Abstract

Background

Clearance of synaptically released glutamate, and hence termination of glutamatergic neurotransmission, is carried out by glutamate transporters, most especially glutamate transporter-1 (GLT-1) and the glutamate-aspartate transporter (GLAST) that are located in astrocytes. It is becoming increasingly well appreciated that changes in the function and expression of GLT-1 and GLAST occur under different physiological and pathological conditions. Here we investigated the plasticity in expression of GLT-1 and GLAST in the spinal dorsal horn using immunohistochemistry following partial sciatic nerve ligation (PSNL) in rats.

Results

Animals were confirmed to develop hypersensitivity to mechanical stimulation by 7 days following PSNL. Baseline expression of GLT-1 and GLAST in naive animals was only observed in astrocytes and not in either microglia or neurons. Microglia and astrocytes showed evidence of reactivity to the nerve injury when assessed at 7 and 14 days following PSNL evidenced by increased expression of OX-42 and GFAP, respectively. In contrast, the total level of GLT-1 and GLAST protein decreased at both 7 and 14 days after PSNL. Importantly, the cellular location of GLT-1 and GLAST was also altered in response to nerve injury. Whereas activated astrocytes showed a marked decrease in expression of GLT-1 and GLAST, activated microglia showed de novo expression of GLT-1 and GLAST at 7 days after PSNL and this was maintained through day 14. Neurons showed no expression of GLT-1 or GLAST at any time point.

Conclusion

These results indicate that the expression of glutamate transporters in astrocytes and microglia are differentially regulated following nerve injury.
Appendix
Available only for authorised users
Literature
1.
go back to reference Mayer ML, Westbrook GL: The physiology of excitatory amino acids in the vertebrate central nervous system. Prog Neurobiol 1987, 28: 197–276. 10.1016/0301-0082(87)90011-6PubMedCrossRef Mayer ML, Westbrook GL: The physiology of excitatory amino acids in the vertebrate central nervous system. Prog Neurobiol 1987, 28: 197–276. 10.1016/0301-0082(87)90011-6PubMedCrossRef
2.
3.
go back to reference Bennett GJ: Update on the neurophysiology of pain transmission and modulation: focus on the NMDA-receptor. J Pain Symptom Manage 2000, 19: S2-S6. 10.1016/S0885-3924(99)00120-7PubMedCrossRef Bennett GJ: Update on the neurophysiology of pain transmission and modulation: focus on the NMDA-receptor. J Pain Symptom Manage 2000, 19: S2-S6. 10.1016/S0885-3924(99)00120-7PubMedCrossRef
4.
go back to reference Bennett GJ: A neuroimmune interaction in painful peripheral neuropathy. Clin J Pain 2000, 16: S139-S143.PubMedCrossRef Bennett GJ: A neuroimmune interaction in painful peripheral neuropathy. Clin J Pain 2000, 16: S139-S143.PubMedCrossRef
5.
go back to reference Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, Kanai Y, Hediger MA, Wang Y, Schielke JP, Welty DF: Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 1996, 16: 675–686. 10.1016/S0896-6273(00)80086-0PubMedCrossRef Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, Kanai Y, Hediger MA, Wang Y, Schielke JP, Welty DF: Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 1996, 16: 675–686. 10.1016/S0896-6273(00)80086-0PubMedCrossRef
6.
go back to reference Wadiche JI, Arriza JL, Amara SG, Kavanaugh MP: Kinetics of a human glutamate transporter. Neuron 1995, 14: 1019–1027. 10.1016/0896-6273(95)90340-2PubMedCrossRef Wadiche JI, Arriza JL, Amara SG, Kavanaugh MP: Kinetics of a human glutamate transporter. Neuron 1995, 14: 1019–1027. 10.1016/0896-6273(95)90340-2PubMedCrossRef
7.
go back to reference Gegelashvili G, Schousboe A: High afinity glutamate transporters: Regulation of expression and activity. Mol Pharmacol 1997, 52: 6–15.PubMed Gegelashvili G, Schousboe A: High afinity glutamate transporters: Regulation of expression and activity. Mol Pharmacol 1997, 52: 6–15.PubMed
8.
go back to reference Lehre KP, Danbolt NC: The number of glutamate transporter subtype molecules at glutamatergic synapses: chemical and stereological quantification in young adult rat brain. J Neurosci 1998, 18: 8751–8757.PubMed Lehre KP, Danbolt NC: The number of glutamate transporter subtype molecules at glutamatergic synapses: chemical and stereological quantification in young adult rat brain. J Neurosci 1998, 18: 8751–8757.PubMed
9.
go back to reference Berger UV, Hediger MA: Distribution of the glutamate transporters GLAST and GLT-1 in rat circumventricular organs, meninges, and dorsal root ganglia. J Comp Neurol 2000, 421: 385–399. 10.1002/(SICI)1096-9861(20000605)421:3<385::AID-CNE7>3.0.CO;2-SPubMedCrossRef Berger UV, Hediger MA: Distribution of the glutamate transporters GLAST and GLT-1 in rat circumventricular organs, meninges, and dorsal root ganglia. J Comp Neurol 2000, 421: 385–399. 10.1002/(SICI)1096-9861(20000605)421:3<385::AID-CNE7>3.0.CO;2-SPubMedCrossRef
10.
go back to reference Sonnewald U, Westergaard N, Schousboe A: Glutamate transport and metabolism in astrocytes. GLIA 1997, 21: 56–63. 10.1002/(SICI)1098-1136(199709)21:1<56::AID-GLIA6>3.0.CO;2-#PubMedCrossRef Sonnewald U, Westergaard N, Schousboe A: Glutamate transport and metabolism in astrocytes. GLIA 1997, 21: 56–63. 10.1002/(SICI)1098-1136(199709)21:1<56::AID-GLIA6>3.0.CO;2-#PubMedCrossRef
11.
go back to reference Liaw WJ, Stephens RL Jr, Binns BC, Chu Y, Sepkuty JP, Johns RA, Rothstein JD, Tao YX: Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord. Pain 2005, 115: 60–70. 10.1016/j.pain.2005.02.006PubMedCrossRef Liaw WJ, Stephens RL Jr, Binns BC, Chu Y, Sepkuty JP, Johns RA, Rothstein JD, Tao YX: Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord. Pain 2005, 115: 60–70. 10.1016/j.pain.2005.02.006PubMedCrossRef
12.
go back to reference Weng HR, Chen JH, Cata JP: Inhibition of glutamate uptake in the spinal cord induces hyperalgesia and increased responses of spinal dorsal horn neurons to peripheral afferent stimulation. Neuroscience 2006, 138: 1351–1360. 10.1016/j.neuroscience.2005.11.061PubMedCrossRef Weng HR, Chen JH, Cata JP: Inhibition of glutamate uptake in the spinal cord induces hyperalgesia and increased responses of spinal dorsal horn neurons to peripheral afferent stimulation. Neuroscience 2006, 138: 1351–1360. 10.1016/j.neuroscience.2005.11.061PubMedCrossRef
13.
go back to reference Sung B, Lim G, Mao J: Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats. J Neurosci 2003, 23: 2899–2910.PubMed Sung B, Lim G, Mao J: Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats. J Neurosci 2003, 23: 2899–2910.PubMed
14.
go back to reference Binns BC, Huang Y, Goettl VM, Hackshaw KV, Stephens RL Jr: Glutamate uptake is attenuated in spinal deep dorsal and ventral horn in the rat spinal nerve ligation model. Brain Res 2005, 1041: 38–47. 10.1016/j.brainres.2005.01.088PubMedCrossRef Binns BC, Huang Y, Goettl VM, Hackshaw KV, Stephens RL Jr: Glutamate uptake is attenuated in spinal deep dorsal and ventral horn in the rat spinal nerve ligation model. Brain Res 2005, 1041: 38–47. 10.1016/j.brainres.2005.01.088PubMedCrossRef
15.
go back to reference Weng HR, Aravindan N, Cata JP, Chen JH, Shaw AD, Dougherty PM: Spinal glial glutamate transporters downregulate in rats with taxol-induced hyperalgesia. Neurosci Lett 2005, 386: 18–22. 10.1016/j.neulet.2005.05.049PubMedCrossRef Weng HR, Aravindan N, Cata JP, Chen JH, Shaw AD, Dougherty PM: Spinal glial glutamate transporters downregulate in rats with taxol-induced hyperalgesia. Neurosci Lett 2005, 386: 18–22. 10.1016/j.neulet.2005.05.049PubMedCrossRef
16.
go back to reference Seltzer Z, Dubner R, Shir Y: A novel behavioral model of neuropathic pain disorders produced by partial sciatic nerve injury. Pain 1990, 43: 205–218. 10.1016/0304-3959(90)91074-SPubMedCrossRef Seltzer Z, Dubner R, Shir Y: A novel behavioral model of neuropathic pain disorders produced by partial sciatic nerve injury. Pain 1990, 43: 205–218. 10.1016/0304-3959(90)91074-SPubMedCrossRef
17.
go back to reference Dougherty PM, Garrison CJ, Carlton SM: Differential influence of local anesthetic upon two models of experimentally-induced peripheral mononeuropathy in the rat. Brain Res 1992, 570: 109–115. 10.1016/0006-8993(92)90570-YPubMedCrossRef Dougherty PM, Garrison CJ, Carlton SM: Differential influence of local anesthetic upon two models of experimentally-induced peripheral mononeuropathy in the rat. Brain Res 1992, 570: 109–115. 10.1016/0006-8993(92)90570-YPubMedCrossRef
18.
go back to reference Storck T, Schulte S, Hofmann K, Stoffel W: Structure, expression, and functional analysis of a Na(+)-dependent glutamate/aspartate transporter from rat brain. Proc Natl Acad Sci USA 1992, 89: 10955–10959. 10.1073/pnas.89.22.10955PubMedCentralPubMedCrossRef Storck T, Schulte S, Hofmann K, Stoffel W: Structure, expression, and functional analysis of a Na(+)-dependent glutamate/aspartate transporter from rat brain. Proc Natl Acad Sci USA 1992, 89: 10955–10959. 10.1073/pnas.89.22.10955PubMedCentralPubMedCrossRef
19.
go back to reference Pines G, Danbolt NC, Bjoras M, Zhang Y, Bendahan A, Eide L, Koepsell H, Storm-Mathisen J, Seeberg E, Kanner BI: Cloning and expression of a rat brain L-glutamate transporter. Nature 1992, 360: 464–467. 10.1038/360464a0PubMedCrossRef Pines G, Danbolt NC, Bjoras M, Zhang Y, Bendahan A, Eide L, Koepsell H, Storm-Mathisen J, Seeberg E, Kanner BI: Cloning and expression of a rat brain L-glutamate transporter. Nature 1992, 360: 464–467. 10.1038/360464a0PubMedCrossRef
20.
go back to reference Tanaka K: Expression cloning of a rat glutamate transporter. Neurosci Res 1993, 16: 149–153. 10.1016/0168-0102(93)90082-2PubMedCrossRef Tanaka K: Expression cloning of a rat glutamate transporter. Neurosci Res 1993, 16: 149–153. 10.1016/0168-0102(93)90082-2PubMedCrossRef
21.
go back to reference Gegelashvili G, Schousboe A: High affinity glutamate transporters: regulation of expression and activity. Mol Pharmacol 1997, 52: 6–15.PubMed Gegelashvili G, Schousboe A: High affinity glutamate transporters: regulation of expression and activity. Mol Pharmacol 1997, 52: 6–15.PubMed
22.
go back to reference Lopez-Redondo F, Nakajima K, Honda S, Kohsaka S: Glutamate transporter GLT-1 is highly expressed in activated microglia following facial nerve axotomy. Brain Res Mol Brain Res 2000, 76: 429–435. 10.1016/S0169-328X(00)00022-XPubMedCrossRef Lopez-Redondo F, Nakajima K, Honda S, Kohsaka S: Glutamate transporter GLT-1 is highly expressed in activated microglia following facial nerve axotomy. Brain Res Mol Brain Res 2000, 76: 429–435. 10.1016/S0169-328X(00)00022-XPubMedCrossRef
23.
go back to reference Tawfik VL, Regan MR, Haenggeli C, Lacroix-Fralish ML, Nutile-McMenemy N, Perez N, Rothstein JD, DeLeo JA: Propentofylline-induced astrocyte modulation leads to alterations in glial glutamate promoter activation following spinal nerve transection. Neuroscience 2008, 152: 1086–1092. 10.1016/j.neuroscience.2008.01.065PubMedCentralPubMedCrossRef Tawfik VL, Regan MR, Haenggeli C, Lacroix-Fralish ML, Nutile-McMenemy N, Perez N, Rothstein JD, DeLeo JA: Propentofylline-induced astrocyte modulation leads to alterations in glial glutamate promoter activation following spinal nerve transection. Neuroscience 2008, 152: 1086–1092. 10.1016/j.neuroscience.2008.01.065PubMedCentralPubMedCrossRef
24.
go back to reference Palecek J, Paleckova V, Dougherty PM, Carlton SM, Willis WD: Responses of spinothalamic tract cells to mechanical and thermal stimulation of the skin in rats with an experimental peripheral neuropathy. J Neurophysiol 1992, 67: 1562–1573.PubMed Palecek J, Paleckova V, Dougherty PM, Carlton SM, Willis WD: Responses of spinothalamic tract cells to mechanical and thermal stimulation of the skin in rats with an experimental peripheral neuropathy. J Neurophysiol 1992, 67: 1562–1573.PubMed
25.
go back to reference Maeda S, Kawamoto A, Yatani Y, Shirakawa H, Nakagawa T, Kaneko S: Gene transfer of GLT-1, a glial glutamate transporter, into the spinal cord by recombinant adenovirus attenuates inflammatory and neuropathic pain in rats. Mol Pain 2008, 4: 65. 10.1186/1744-8069-4-65PubMedCentralPubMedCrossRef Maeda S, Kawamoto A, Yatani Y, Shirakawa H, Nakagawa T, Kaneko S: Gene transfer of GLT-1, a glial glutamate transporter, into the spinal cord by recombinant adenovirus attenuates inflammatory and neuropathic pain in rats. Mol Pain 2008, 4: 65. 10.1186/1744-8069-4-65PubMedCentralPubMedCrossRef
26.
go back to reference Garrison CJ, Dougherty PM, Kajander KC, Carlton SM: Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury. Brain Res 1991, 565: 1–7. 10.1016/0006-8993(91)91729-KPubMedCrossRef Garrison CJ, Dougherty PM, Kajander KC, Carlton SM: Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury. Brain Res 1991, 565: 1–7. 10.1016/0006-8993(91)91729-KPubMedCrossRef
27.
go back to reference Ma W, Quirion R: Partial sciatic nerve ligation induces increase in the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in astrocytes in the lumbar spinal dorsal horn and the gracile nucleus. Pain 2002, 99: 175–184. 10.1016/S0304-3959(02)00097-0PubMedCrossRef Ma W, Quirion R: Partial sciatic nerve ligation induces increase in the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in astrocytes in the lumbar spinal dorsal horn and the gracile nucleus. Pain 2002, 99: 175–184. 10.1016/S0304-3959(02)00097-0PubMedCrossRef
28.
go back to reference Watkins LR, Milligan ED, Maier SF: Glial activation: a driving force for pathological pain. Trends Neurosci 2001, 24: 450–455. 10.1016/S0166-2236(00)01854-3PubMedCrossRef Watkins LR, Milligan ED, Maier SF: Glial activation: a driving force for pathological pain. Trends Neurosci 2001, 24: 450–455. 10.1016/S0166-2236(00)01854-3PubMedCrossRef
29.
go back to reference Aldskogius H, Kozlova EN: Central neuron-glial and glial-glial interactions following axon injury. Prog Neurobiol 1998, 55: 1–26. 10.1016/S0301-0082(97)00093-2PubMedCrossRef Aldskogius H, Kozlova EN: Central neuron-glial and glial-glial interactions following axon injury. Prog Neurobiol 1998, 55: 1–26. 10.1016/S0301-0082(97)00093-2PubMedCrossRef
30.
go back to reference Curtis R, Tonra JR, Stark JL, Adryan KM, Park JS, Cliffer KD, Lindsay RM, DiStefano PS: Neuronal injury increases retrograde axonal transport of the neurotrophins to spinal sensory neurons and motor neurons via multiple receptor mechanisms. Mol Cell Neurosci 1998, 12: 105–118. 10.1006/mcne.1998.0704PubMedCrossRef Curtis R, Tonra JR, Stark JL, Adryan KM, Park JS, Cliffer KD, Lindsay RM, DiStefano PS: Neuronal injury increases retrograde axonal transport of the neurotrophins to spinal sensory neurons and motor neurons via multiple receptor mechanisms. Mol Cell Neurosci 1998, 12: 105–118. 10.1006/mcne.1998.0704PubMedCrossRef
31.
go back to reference Cameron AA, Cliffer KD, Dougherty PM, Garrison CJ, Willis WD, Carlton SM: Time course of degenerative and regenerative changes in the dorsal horn in a rat model of peripheral neuropathy. J Comp Neurol 1997, 379: 428–442. 10.1002/(SICI)1096-9861(19970317)379:3<428::AID-CNE8>3.0.CO;2-5PubMedCrossRef Cameron AA, Cliffer KD, Dougherty PM, Garrison CJ, Willis WD, Carlton SM: Time course of degenerative and regenerative changes in the dorsal horn in a rat model of peripheral neuropathy. J Comp Neurol 1997, 379: 428–442. 10.1002/(SICI)1096-9861(19970317)379:3<428::AID-CNE8>3.0.CO;2-5PubMedCrossRef
32.
go back to reference Cameron AA, Dougherty PM, Garrison CJ, Willis WD, Carlton SM: The endogenous lectin RL-29 is transynaptically induced in dorsal horn neurons following peripheral neuropathy in the rat. Brain Res 1993, 620: 64–71. 10.1016/0006-8993(93)90271-NPubMedCrossRef Cameron AA, Dougherty PM, Garrison CJ, Willis WD, Carlton SM: The endogenous lectin RL-29 is transynaptically induced in dorsal horn neurons following peripheral neuropathy in the rat. Brain Res 1993, 620: 64–71. 10.1016/0006-8993(93)90271-NPubMedCrossRef
33.
go back to reference Cameron AA, Cliffer KD, Dougherty PM, Willis WD, Carlton SM: Changes in lectin, GAP-43 and neuropeptide staining in the rat superficial dorsal horn following experimental peripheral neuropathy. Neurosci Lett 1991, 131: 249–252. 10.1016/0304-3940(91)90625-4PubMedCrossRef Cameron AA, Cliffer KD, Dougherty PM, Willis WD, Carlton SM: Changes in lectin, GAP-43 and neuropeptide staining in the rat superficial dorsal horn following experimental peripheral neuropathy. Neurosci Lett 1991, 131: 249–252. 10.1016/0304-3940(91)90625-4PubMedCrossRef
34.
go back to reference Swanson RA, Liu J, Miller JW, Rothstein JD, Farrell K, Stein BA, Longuemare MC: Neuronal regulation of glutamate transporter subtype expression in astrocytes. J Neurosci 1997, 17: 932–940.PubMed Swanson RA, Liu J, Miller JW, Rothstein JD, Farrell K, Stein BA, Longuemare MC: Neuronal regulation of glutamate transporter subtype expression in astrocytes. J Neurosci 1997, 17: 932–940.PubMed
35.
go back to reference Cata JP, Weng HR, Dougherty PM: The effects of thalidomide and minocycline on taxol-induced hyperalgesia in rats. Brain Res 2008, 1229: 100–110. 10.1016/j.brainres.2008.07.001PubMedCentralPubMedCrossRef Cata JP, Weng HR, Dougherty PM: The effects of thalidomide and minocycline on taxol-induced hyperalgesia in rats. Brain Res 2008, 1229: 100–110. 10.1016/j.brainres.2008.07.001PubMedCentralPubMedCrossRef
36.
go back to reference Xin WJ, Gong QJ, Xu JT, Yang HW, Zang Y, Zhang T, Li YY, Liu XG: Role of phosphorylation of ERK in induction and maintenance of LTP of the C-fiber evoked field potentials in spinal dorsal horn. J Neurosci Res 2006, 84: 934–943. 10.1002/jnr.21013PubMedCrossRef Xin WJ, Gong QJ, Xu JT, Yang HW, Zang Y, Zhang T, Li YY, Liu XG: Role of phosphorylation of ERK in induction and maintenance of LTP of the C-fiber evoked field potentials in spinal dorsal horn. J Neurosci Res 2006, 84: 934–943. 10.1002/jnr.21013PubMedCrossRef
Metadata
Title
Plasticity in expression of the glutamate transporters GLT-1 and GLAST in spinal dorsal horn glial cells following partial sciatic nerve ligation
Authors
Wen-Jun Xin
Han-Rong Weng
Patrick M Dougherty
Publication date
01-12-2009
Publisher
BioMed Central
Published in
Molecular Pain / Issue 1/2009
Electronic ISSN: 1744-8069
DOI
https://doi.org/10.1186/1744-8069-5-15

Other articles of this Issue 1/2009

Molecular Pain 1/2009 Go to the issue