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 brainderived 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 ϩ 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 ϩ/ϩ (WT) and trkB.T1 Ϫ/Ϫ (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.

Astrocyte truncated tropomyosin receptor kinase B mediates brain‐derived neurotrophic factor anti‐apoptotic effect leading to neuroprotection

“…TrkB-T1 mediates BDNF-induced internalization of glycine transporters in astrocytes (Aroeira et al 2015) and modulates GABA transporters (Vaz et al 2011). A recent report describes that TrkB-T1 knockout mice-derived astrocytes exhibit decreased migration and proliferation in vitro (Matyas et al 2017). In line with these reports, our results suggest involvement of TrkB-T1 in BDNF protective effects, and show for the first time the protective role of astrocyte TrkB by mediating BDNF effects.…”

Visualizing BDNF cell-to-cell transfer reveals astrocytes are the primary recipient of neuronal BDNF

“…This finding is further supported by a previous report that addition of recombinant BDNF to astrocyte monocultures increases cell area via TrkB.T1 mediated Rho GTPase activity (Ohira et al, 2005). In addition, following spinal cord injury, TrkB.T1 knockout astrocytes have slower migration/proliferation in response to BDNF and downregulated migration and proliferation pathways (Matyas et al, 2017). Interestingly, BDNF, TrkB, and astrocytic territory are all increased by exercise (Fahimi et al, 2017), which enhances cognition (Gomez-Pinilla and Hillman, 2013).…”

Dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might contribute to postoperative cognitive dysfunction in aging mice

“…In a mouse model of Down syndrome, the accelerated death of hippocampal neurons is not rescued by exogenous BDNF delivery [12] but instead by restoring the physiological levels of TrkB.T1 [56]. In a mouse model of spinal cord injury, the increased levels of TrkB.T1 contribute to locomotor dysfunction and neuropathic pain [57]. In the present study, we showed that expression of TrkB-FL was significantly decreased after anesthesia and surgery, whereas TrkB-ICD was significantly increased.…”