Involvement of NT3 and P75(NTR) in photoreceptor degeneration following selective Müller cell ablation

BACKGROUND: Neurotrophins can regulate opposing functions that result in cell survival or apoptosis, depending on which form of the protein is secreted and which receptor and signaling pathway is activated. We have recently developed a transgenic model in which inducible and patchy Müller cell ablation leads to photoreceptor degeneration. This study aimed to examine the roles of mature neurotrophin-3 (NT3), pro-NT3 and p75 neurotrophin receptor (P75(NTR)) in photoreceptor degeneration in this model. METHODS: Transgenic mice received tamoxifen to induce Müller cell ablation. Changes in the status of Müller and microglia cells as well as expression of mature NT3, pro-NT3 and P75(NTR) were examined by immunohistochemistry and Western blot analysis. Recombinant mature NT3 and an antibody neutralizing 75(NTR) were injected intravitreally 3 and 6 days after Müller cell ablation to examine their effects on photoreceptor degeneration and microglial activation. RESULTS: We found that patchy loss of Müller cells was associated with activation of surviving Müller cells and microglial cells, concurrently with reduced expression of mature NT3 and upregulation of pro-NT3 and P75(NTR). Intravitreal injection of mature NT3 and a neutralizing antibody to P75(NTR), either alone or in combination, attenuated photoreceptor degeneration and the beneficial effect was associated with inhibition of microglial activation. CONCLUSIONS: Our data suggest that Müller cell ablation alters the balance between the protective and deleterious effects of mature NT3 and pro-NT3. Modulation of the neuroprotective action of mature NT3 and pro-apoptotic pro-NT3/P75(NTR) signaling may represent a novel pharmacological strategy for photoreceptor protection in retinal disease.