TrkB signaling in Müller glia stimulates neuroprotection after optic nerve injury

Abstract

PurposeBrain‐derived neurotrophic factor (BDNF) is a neurotrophic factor that regulates neural cell survival mainly by activating TrkB receptors. Several lines of evidence support a key role for BDNF‐TrkB signaling in survival of adult retinal ganglion cells (RGCs) in acute and chronic models of optic nerve damage. On the other hand, glial cells have recently attracted considerable attention as mediators of neural cell survival. To further elucidate the role of glial cells in BDNF‐mediated neuroprotection, we examined the effect of optic nerve injury (ONI) on TrkBGFAP KO mice, in which TrkB is deleted in retinal glial cells.MethodsWe examined the effect of ONI in WT and TrkBGFAP KO mice at day (d) 7 and 14 after ONI by spectral‐domain optical coherence tomography (SD‐OCT), retrograde labeling of RGCs, immunohistochemistry and quantitative real‐time PCR analyses.ResultsONI‐induced RGC loss and retinal degeneration occurred quickly in TrkBGFAP KO mice at d7 after ONI, but the severity was comparable with WT mice at d14. We next examined the effects of ONI on the production of trophic factors in the retina. ONI markedly increased mRNA expression levels of basic fibroblast growth factor (bFGF) in WT mice at d3, but not in TrkBGFAP KO mice. Immunohistochemical analysis at d7 revealed that ONI induced bFGF upregulation mainly in Müller glia. On the other hand, glial cell line‐derived neurotrophic factor (GDNF) expression level was slightly decreased in TrkBGFAP KO mice compared with WT mice at d3, but not at d10.ConclusionsThese results demonstrate that BDNF signaling in retinal glia plays important roles in the early stage of neural protection after traumatic injury. Additionally, our genetic models provide a system in which glia‐specific gene functions can be examined in central nervous system tissues in vivo.