title: Truncated TrkB.T1-Mediated Astrocyte Dysfunction Contributes to Impaired Motor Function and Neuropathic Pain after Spinal Cord Injury.
abstract: Following spinal cord injury (SCI), astrocytes demonstrate long-lasting reactive changes, which are associated with the persistence of neuropathic pain and motor dysfunction. We previously demonstrated that upregulation of trkB.T1, a truncated isoform of the brain-derived neurotrophic factor receptor (BDNF), contributes to gliosis after SCI, but little is known about the effects of trkB.T1 on the function of astrocytes. As trkB.T1 is the sole isoform of trkB receptors expressed on astrocytes, we examined the function of trkB.T1-driven astrocytesin vitroandin vivoImmunohistochemistry showed that trkB.T1+cells were significantly upregulated 7 d after injury, with sustained elevation in white matter through 8 weeks. The latter increase was predominantly found in astrocytes. TrkB.T1 was also highly expressed by neurons and microglia/macrophages at 7 d after injury and declined by 8 weeks. RNA sequencing of cultured astrocytes derived fromtrkB.T1+/+(WT) andtrkB.T1-/-(KO) mice revealed downregulation of migration and proliferation pathways in KO astrocytes. KO astrocytes also exhibited slower migration/proliferationin vitroin response to FBS or BDNF compared with WT astrocytes. Reduced proliferation of astrocytes was also confirmed after SCI in astrocyte-specifictrkB.T1KO mice; using mechanical allodynia and pain-related measurements on the CatWalk, these animals also showed reduced hyperpathic responses, along with improved motor coordination. Together, our data indicate that trkB.T1 in astrocytes contributes to neuropathic pain and neurological dysfunction following SCI, suggesting that trkB.T1 may provide a novel therapeutic target for SCI.SIGNIFICANCE STATEMENTNeuropathic pain after spinal cord injury (SCI) may in part be caused by upregulation of the brain-derived neurotrophic factor (BDNF) receptor trkB.T1, a truncated isoform of BDNF. TrkB.T1 is the only isoform of tropomyosin-related receptor kinase type B (trkB) receptors expressed on astrocytes. Here, we showed that trkB.T1 is significantly increased in the injured mouse spinal cord, where it is predominantly found in astrocytes. RNA sequencing of cultured astrocytes demonstrated downregulation of migration and proliferation pathways intrkB.T1KO astrocytes. This was validatedin vivo, where deletion oftrkB.T1in astrocytes reduced cell proliferation and migration. After SCI, astrocyte-specifictrkB.T1KO mice showed reduced hyperpathic responses and improved motor coordination. Therefore, the trkB.T1 receptor plays a significant pathophysiological role after SCI, and may provide a novel therapeutic target for SCI.
authors.affiliation: Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, School of Medicine.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Matyas
authors.affiliation: Department of Pain and Translational Symptom Science, School of Nursing.
authors.forename: Cliona M
authors.initials: CM
authors.lastname: O'Driscoll
authors.affiliation: Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, School of Medicine.
authors.forename: Laina
authors.identifier: 0000-0002-7922-5370
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, School of Medicine.
authors.forename: Marina
authors.initials: M
authors.lastname: Coll-Miro
authors.affiliation: Institute for Genome Sciences, School of Medicine.
authors.forename: Sean
authors.initials: S
authors.lastname: Daugherty
authors.affiliation: Department of Pain and Translational Symptom Science, School of Nursing.|Program in Neuroscience, and.|University of Maryland Center to Advance Chronic Pain Research, University of Maryland, Baltimore, Maryland 21201.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Renn
authors.affiliation: Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, School of Medicine.|Program in Neuroscience, and.|University of Maryland Center to Advance Chronic Pain Research, University of Maryland, Baltimore, Maryland 21201.
authors.forename: Alan I
authors.identifier: 0000-0003-0128-2348
authors.initials: AI
authors.lastname: Faden
authors.affiliation: Department of Pain and Translational Symptom Science, School of Nursing, jwu@anes.umm.edu sdorsey@son.umaryland.edu.|Program in Neuroscience, and.|University of Maryland Center to Advance Chronic Pain Research, University of Maryland, Baltimore, Maryland 21201.
authors.forename: Susan G
authors.identifier: 0000-0001-7648-1312
authors.initials: SG
authors.lastname: Dorsey
authors.affiliation: Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, School of Medicine, jwu@anes.umm.edu sdorsey@son.umaryland.edu.|Program in Neuroscience, and.|University of Maryland Center to Advance Chronic Pain Research, University of Maryland, Baltimore, Maryland 21201.
authors.forename: Junfang
authors.initials: J
authors.lastname: Wu
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology*; D009437:Neuralgia / Q000378:metabolism* / Q000503:physiopathology; D020033:Protein Isoforms / Q000378:metabolism; D020813:Receptor, trkB / Q000172:deficiency / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D020033:Protein Isoforms; D020813:Receptor, trkB
keywords: astrocytes; brain-derived neurotrophic factor; neuropathic pain; spinal cord injury; trkB.T1