GLT1 overexpression reverses established neuropathic pain-related behavior and attenuates chronic dorsal horn neuron activation following cervical spinal cord injury.
Development of neuropathic pain occurs in a major portion of traumatic spinal cord injury (SCI) patients, resulting in debilitating and often long-term physical and psychological burdens. Following SCI, chronic dysregulation of extracellular glutamate homeostasis has been shown to play a key role in persistent central hyperexcitability of superficial dorsal horn neurons that mediate pain neurotransmission, leading to various forms of neuropathic pain. Astrocytes express the major CNS glutamate transporter, GLT1, which is responsible for the vast majority of functional glutamate uptake, particularly in the spinal cord. In our unilateral cervical contusion model of mouse SCI that is associated with ipsilateral forepaw heat hypersensitivity (a form of chronic at-level neuropathic pain-related behavior), we previously reported significant and long-lasting reductions in GLT1 expression and functional GLT1-mediated glutamate uptake in cervical spinal cord dorsal horn. To therapeutically address GLT1 dysfunction following cervical contusion SCI, we injected an adeno-associated virus type 8 (AAV8)-Gfa2 vector into the superficial dorsal horn to increase GLT1 expression selectively in astrocytes. Compared to both contusion-only animals and injured mice that received AAV8-eGFP control injection, AAV8-GLT1 delivery increased GLT1 protein expression in astrocytes of the injured cervical spinal cord dorsal horn, resulting in a significant and persistent reversal of already-established heat hypersensitivity. Furthermore, AAV8-GLT1 injection significantly reduced expression of the transcription factor and marker of persistently increased neuronal activation, ΔFosB, in superficial dorsal horn neurons. These results demonstrate that focal restoration of GLT1 expression in the superficial dorsal horn is a promising target for treating chronic neuropathic pain following SCI.
Department of Neuroscience, Farber Institute for Neurosciences, Sidney Kimmel Medical College at Thomas Jefferson University, 900 Walnut Street, JHN 469, Philadelphia, Pennsylvania.
Aditi
A
Falnikar
Department of Neuroscience, Farber Institute for Neurosciences, Sidney Kimmel Medical College at Thomas Jefferson University, 900 Walnut Street, JHN 469, Philadelphia, Pennsylvania.
Tamara J
TJ
Hala
Department of Neurosurgery, University at Buffalo, SUNY-School of Medicine and Biomedical Sciences, Buffalo, New York.
David J
DJ
Poulsen
Department of Neuroscience, Farber Institute for Neurosciences, Sidney Kimmel Medical College at Thomas Jefferson University, 900 Walnut Street, JHN 469, Philadelphia, Pennsylvania.
Angelo C
AC
Lepore
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D066193:Cervical Cord; D004195:Disease Models, Animal; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism*; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000473:pathology; D053580:Muscle Strength / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009437:Neuralgia / Q000209:etiology*; D000076104:Oligodendrocyte Transcription Factor 2; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D017288:Pain Threshold / Q000502:physiology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D020671:Posterior Horn Cells / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000150:complications* / Q000473:pathology*; D014404:Tubulin / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D016761:Oncogene Proteins v-fos; D010751:Phosphopyruvate Hydratase; D014404:Tubulin; C512773:Olig2 protein, mouse; C493396:Slc1a2 protein, mouse; C462941:beta3 tubulin, mouse
adeno-associated virus; astrocyte; contusion; glutamate transporter; neuropathic pain