Tackling Glaucoma from within the Brain: An Unfortunate Interplay of BDNF and TrkB.

Eline Dekeyster,Manuel Salinas-Navarro,Veerle Baekelandt,Tom Buyens,Lieve Moons,Chris Van Den Haute,Emiel Geeraerts,Lies De Groef,Tudor C Badea

doi:10.1371/journal.pone.0142067

Abstract

According to the neurotrophin deprivation hypothesis, diminished retrograde delivery of neurotrophic support during an early stage of glaucoma pathogenesis is one of the main triggers that induce retinal ganglion cell (RGC) degeneration. Therefore, interfering with neurotrophic signaling seems an attractive strategy to achieve neuroprotection. Indeed, exogenous neurotrophin administration to the eye has been shown to reduce loss of RGCs in animal models of glaucoma; however, the neuroprotective effect was mostly insufficient for sustained RGC survival. We hypothesized that treatment at the level of neurotrophin-releasing brain areas might be beneficial, as signaling pathways activated by target-derived neurotrophins are suggested to differ from pathways that are initiated at the soma membrane. In our study, first, the spatiotemporal course of RGC degeneration was characterized in mice subjected to optic nerve crush (ONC) or laser induced ocular hypertension (OHT). Subsequently, the well-known neurotrophin brain-derived neurotrophic factor (BDNF) was chosen as the lead molecule, and the levels of BDNF and its high-affinity receptor, tropomyosin receptor kinase B (TrkB), were examined in the mouse retina and superior colliculus (SC) upon ONC and OHT. Both models differentially influenced BDNF and TrkB levels. Next, we aimed for RGC protection through viral vector-mediated upregulation of collicular BDNF, thought to boost the retrograde neurotrophin delivery. Although the previously reported temporary neuroprotective effect of intravitreally delivered recombinant BDNF was confirmed, viral vector-induced BDNF overexpression in the SC did not result in protection of the RGCs in the glaucoma models used. These findings most likely relate to decreased neurotrophin responsiveness upon vector-mediated BDNF overexpression. Our results highlight important insights concerning the complexity of neurotrophic factor treatments that should surely be considered in future neuroprotective strategies.

Highlights

Glaucomatous optic neuropathies are characterized by degeneration of retinal ganglion cells (RGCs) and their axons, resulting in visual field defects[1,2,3]
The optic nerve crush (ONC) induced with self-closing cross-action forceps resulted in a complete crush of the optic nerve and all RGC axons, as visualized by hematoxylin and eosin staining and RT97 IHC on optic nerve cross-sections, harvested at 1 h after ONC
ONCinduced RGC degeneration was diffuse throughout the retina (Fig 1B)

Summary

Introduction

Glaucomatous optic neuropathies are characterized by degeneration of retinal ganglion cells (RGCs) and their axons, resulting in visual field defects[1,2,3]. The neurotrophin deprivation hypothesis proposes that diminished retrograde transport, resulting in deprivation of brainderived neurotrophic support to the RGCs, is one of the triggers that induces glaucomatous retinal cell death[5, 6]. Based on this theory, various experimental strategies have sought to supply exogenous neurotrophins to curb glaucomatous neurodegeneration[6]. Binding of BDNF to TrkB-FL induces receptor dimerization and transphosphorylation, leading to activation of intracellular signaling pathways involved in cell viability[18]. More recently, TrkB-T1 has, for example, been linked to a complex web of intracellular glial signaling pathways, as well as to regulation of extracellular BDNF concentrations through sequestration [22]

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