Reduction in Expression of the Astrocyte Glutamate Transporter, GLT1, Worsens Functional and Histological Outcomes Following Traumatic Spinal Cord Injury

Overview

Journal Glia

Specialty Neurology

Date 2011 Sep 2

PMID 21882244

Citations 32

Authors

Angelo C Lepore

John ODonnell

Andrew S Kim

Eun Ju Yang

Alisha Tuteja

Amanda Haidet-Phillips

Colin P OBanion

Nicholas J Maragakis

Affiliations

Soon will be listed here.

Abstract

The astrocyte glutamate transporter, GLT1, is responsible for the vast majority of glutamate uptake in the adult central nervous system (CNS), thereby regulating extracellular glutamate homeostasis and preventing excitotoxicity. Glutamate dysregulation plays a central role in outcome following traumatic spinal cord injury (SCI). To determine the role of GLT1 in secondary cell loss following SCI, mice heterozygous for the GLT1 astrocyte glutamate transporter (GLT1+/-) and wild-type mice received thoracic crush SCI. Compared with wild-type controls, GLT1+/- mice had an attenuated recovery in hindlimb motor function, increased lesion size, and decreased tissue sparing. GLT1+/- mice showed a decrease in intraspinal GLT1 protein and functional glutamate uptake compared with wild-type mice, accompanied by increased apoptosis and neuronal loss following crush injury. These results suggest that astrocyte GLT1 plays a role in limiting secondary cell death following SCI, and also show that compromise of key astrocyte functions has significant effects on outcome following traumatic CNS injury. These findings also suggest that increasing intraspinal GLT1 expression may represent a therapeutically relevant target for SCI treatment.

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References

Mu X, Azbill R, Springer J . NBQX treatment improves mitochondrial function and reduces oxidative events after spinal cord injury. J Neurotrauma. 2002; 19(8):917-27. DOI: 10.1089/089771502320317078. View

Agrawal S, Fehlings M . Role of NMDA and non-NMDA ionotropic glutamate receptors in traumatic spinal cord axonal injury. J Neurosci. 1997; 17(3):1055-63. PMC: 6573164. View

Hulsebosch C . Gliopathy ensures persistent inflammation and chronic pain after spinal cord injury. Exp Neurol. 2008; 214(1):6-9. PMC: 2888707. DOI: 10.1016/j.expneurol.2008.07.016. View

Gaviria M, Privat A, DArbigny P, Kamenka J, Haton H, Ohanna F . Neuroprotective effects of a novel NMDA antagonist, Gacyclidine, after experimental contusive spinal cord injury in adult rats. Brain Res. 2000; 874(2):200-9. DOI: 10.1016/s0006-8993(00)02581-6. View

Xu G, Hughes M, Zhang L, Cain L, McAdoo D . Administration of glutamate into the spinal cord at extracellular concentrations reached post-injury causes functional impairments. Neurosci Lett. 2005; 384(3):271-6. DOI: 10.1016/j.neulet.2005.04.100. View

Cao H, Zhang Y . Spinal glial activation contributes to pathological pain states. Neurosci Biobehav Rev. 2008; 32(5):972-83. DOI: 10.1016/j.neubiorev.2008.03.009. View

Faulkner J, Herrmann J, Woo M, Tansey K, Doan N, Sofroniew M . Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci. 2004; 24(9):2143-55. PMC: 6730429. DOI: 10.1523/JNEUROSCI.3547-03.2004. View

Rothstein J, Patel S, Regan M, Haenggeli C, Huang Y, Bergles D . Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature. 2005; 433(7021):73-7. DOI: 10.1038/nature03180. View

Yi J, Hazell A . Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury. Neurochem Int. 2006; 48(5):394-403. DOI: 10.1016/j.neuint.2005.12.001. View

10.

Basso D, Fisher L, Anderson A, Jakeman L, McTigue D, Popovich P . Basso Mouse Scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains. J Neurotrauma. 2006; 23(5):635-59. DOI: 10.1089/neu.2006.23.635. View

11.

Li S, Mealing G, Morley P, Stys P . Novel injury mechanism in anoxia and trauma of spinal cord white matter: glutamate release via reverse Na+-dependent glutamate transport. J Neurosci. 1999; 19(14):RC16. PMC: 6783104. View

12.

Park E, Velumian A, Fehlings M . The role of excitotoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration. J Neurotrauma. 2004; 21(6):754-74. DOI: 10.1089/0897715041269641. View

13.

Xu G, Hughes M, Ye Z, Hulsebosch C, McAdoo D . Concentrations of glutamate released following spinal cord injury kill oligodendrocytes in the spinal cord. Exp Neurol. 2004; 187(2):329-36. DOI: 10.1016/j.expneurol.2004.01.029. View

14.

Rosenberg L, Teng Y, Wrathall J . 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline reduces glial loss and acute white matter pathology after experimental spinal cord contusion. J Neurosci. 1998; 19(1):464-75. PMC: 6782398. View

15.

Stys P . White matter injury mechanisms. Curr Mol Med. 2004; 4(2):113-30. DOI: 10.2174/1566524043479220. View

16.

Liu D, Thangnipon W, McAdoo D . Excitatory amino acids rise to toxic levels upon impact injury to the rat spinal cord. Brain Res. 1991; 547(2):344-8. DOI: 10.1016/0006-8993(91)90984-4. View

17.

Panter S, Yum S, Faden A . Alteration in extracellular amino acids after traumatic spinal cord injury. Ann Neurol. 1990; 27(1):96-9. DOI: 10.1002/ana.410270115. View

18.

Vera-Portocarrero L, Mills C, Ye Z, Fullwood S, McAdoo D, Hulsebosch C . Rapid changes in expression of glutamate transporters after spinal cord injury. Brain Res. 2002; 927(1):104-10. DOI: 10.1016/s0006-8993(01)03329-7. View

19.

Holtz A, Gerdin B . MK 801, an OBS N-methyl-D-aspartate channel blocker, does not improve the functional recovery nor spinal cord blood flow after spinal cord compression in rats. Acta Neurol Scand. 1991; 84(4):334-8. DOI: 10.1111/j.1600-0404.1991.tb04964.x. View

20.

Paul C, Samdani A, Betz R, Fischer I, Neuhuber B . Grafting of human bone marrow stromal cells into spinal cord injury: a comparison of delivery methods. Spine (Phila Pa 1976). 2009; 34(4):328-34. PMC: 3073497. DOI: 10.1097/BRS.0b013e31819403ce. View