PMID- 28270575 OWN - NLM STAT- MEDLINE DCOM- 20170727 LR - 20181113 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 37 IP - 14 DP - 2017 Apr 5 TI - Truncated TrkB.T1-Mediated Astrocyte Dysfunction Contributes to Impaired Motor Function and Neuropathic Pain after Spinal Cord Injury. PG - 3956-3971 LID - 10.1523/JNEUROSCI.3353-16.2017 [doi] AB - 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 astrocytes in vitro and in vivo Immunohistochemistry 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 from trkB.T1(+/+) (WT) and trkB.T1(-/-) (KO) mice revealed downregulation of migration and proliferation pathways in KO astrocytes. KO astrocytes also exhibited slower migration/proliferation in vitro in response to FBS or BDNF compared with WT astrocytes. Reduced proliferation of astrocytes was also confirmed after SCI in astrocyte-specific trkB.T1 KO 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 STATEMENT Neuropathic 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 in trkB.T1 KO astrocytes. This was validated in vivo, where deletion of trkB.T1 in astrocytes reduced cell proliferation and migration. After SCI, astrocyte-specific trkB.T1 KO 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. CI - Copyright (c) 2017 the authors 0270-6474/17/373957-16$15.00/0. FAU - Matyas, Jessica J AU - Matyas JJ AD - Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, School of Medicine. FAU - O'Driscoll, Cliona M AU - O'Driscoll CM AD - Department of Pain and Translational Symptom Science, School of Nursing. FAU - Yu, Laina AU - Yu L AUID- ORCID: 0000-0002-7922-5370 AD - Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, School of Medicine. FAU - Coll-Miro, Marina AU - Coll-Miro M AD - Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, School of Medicine. FAU - Daugherty, Sean AU - Daugherty S AD - Institute for Genome Sciences, School of Medicine. FAU - Renn, Cynthia L AU - Renn CL AD - Department of Pain and Translational Symptom Science, School of Nursing. AD - Program in Neuroscience, and. AD - University of Maryland Center to Advance Chronic Pain Research, University of Maryland, Baltimore, Maryland 21201. FAU - Faden, Alan I AU - Faden AI AUID- ORCID: 0000-0003-0128-2348 AD - Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, School of Medicine. AD - Program in Neuroscience, and. AD - University of Maryland Center to Advance Chronic Pain Research, University of Maryland, Baltimore, Maryland 21201. FAU - Dorsey, Susan G AU - Dorsey SG AUID- ORCID: 0000-0001-7648-1312 AD - Department of Pain and Translational Symptom Science, School of Nursing, jwu@anes.umm.edu sdorsey@son.umaryland.edu. AD - Program in Neuroscience, and. AD - University of Maryland Center to Advance Chronic Pain Research, University of Maryland, Baltimore, Maryland 21201. FAU - Wu, Junfang AU - Wu J AD - Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, School of Medicine, jwu@anes.umm.edu sdorsey@son.umaryland.edu. AD - Program in Neuroscience, and. AD - University of Maryland Center to Advance Chronic Pain Research, University of Maryland, Baltimore, Maryland 21201. LA - eng GR - R01 NR013601/NR/NINR NIH HHS/United States GR - R01 NS094527/NS/NINDS NIH HHS/United States GR - T32 HL007698/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20170307 PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Protein Isoforms) RN - EC 2.7.10.1 (Receptor, trkB) SB - IM MH - Animals MH - Astrocytes/*metabolism MH - Brain-Derived Neurotrophic Factor/metabolism MH - Cell Movement/physiology MH - Cells, Cultured MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Motor Activity/*physiology MH - Neuralgia/*metabolism/physiopathology MH - Protein Isoforms/metabolism MH - Receptor, trkB/deficiency/*metabolism MH - Spinal Cord Injuries/*metabolism/physiopathology PMC - PMC5394902 OTO - NOTNLM OT - astrocytes OT - brain-derived neurotrophic factor OT - neuropathic pain OT - spinal cord injury OT - trkB.T1 EDAT- 2017/03/09 06:00 MHDA- 2017/07/28 06:00 PMCR- 2017/10/05 CRDT- 2017/03/09 06:00 PHST- 2016/10/30 00:00 [received] PHST- 2017/02/03 00:00 [revised] PHST- 2017/02/08 00:00 [accepted] PHST- 2017/03/09 06:00 [pubmed] PHST- 2017/07/28 06:00 [medline] PHST- 2017/03/09 06:00 [entrez] PHST- 2017/10/05 00:00 [pmc-release] AID - JNEUROSCI.3353-16.2017 [pii] AID - 3353-16 [pii] AID - 10.1523/JNEUROSCI.3353-16.2017 [doi] PST - ppublish SO - J Neurosci. 2017 Apr 5;37(14):3956-3971. doi: 10.1523/JNEUROSCI.3353-16.2017. Epub 2017 Mar 7.