Loss of neuroserpin exacerbates retinal ganglion cell dysfunction in neuroserpin knockout mice following chronic increase in intraocular pressure

Abstract

AbstractPurpose: Recent studies have shown neuroserpin (NS) plays a critical role in several neurodegenerative diseases. The neuroprotective role of NS administration in the retina has been reported in an ischemic/reperfusion mouse model of glaucoma. Here, we studied the effect of neuroserpin loss on retinal integrity in normal and experimental glaucoma condition in NS knockout (NS−/−) mice.Methods: NS−/− and C57BL/6J wild type (WT) mice were subjected to weekly intraocular microbead injection for 8‐weeks (n = 40). Positive scotopic threshold response (pSTR) at −4.3log cd s/m2 and electroretinography (ERG) at 3.1 log cd s/m2 were recorded using Phoenix Ganzfeld at the 8‐week time point. Eye and optic nerve (ON) tissues were harvested after 8‐weeks for histological analysis (retina‐ haematoxylin and eosin and ON‐ toluidine blue staining) and biochemical evaluation.Results: NS−/− mice showed significant decline in pSTR amplitude (p < 0.0001) with loss of no. of cells in GCL (p < 0.0001) compared to WT in both normal and glaucoma (IOP: 28.5 ± 1.97 mmHg) conditions. However, no change in whole retinal scotopic ERG was observed in NS−/− and WT mice in both conditions. Plasmin inhibitory assay showed the loss of NS inhibitory activity in NS−/− retinas with or without glaucoma (p < 0.004). ON histology staining showed significant loss of axonal density (p < 0.0001) in NS−/− mice compared to WT in normal condition, however glaucoma exacerbated axonal loss in NS−/− compared to WT mice. Increased expression of autophagy markers, Beclin1 and LC3II/I were confirmed in NS−/− retinal lysates in both normal and glaucoma conditions. TUNEL positive cells were significantly higher in the GCL of retinal sections of NS−/− mice in glaucoma (p < 0.002).Conclusions: NS ablation worsens inner retinal structural and functional damage in glaucoma. This study establishes that absence of neuroserpin in the experimental glaucoma mice increases autophagic response in degenerating retinal cells. The exact molecular mechanism of neuroserpin on autophagy remains undefined. Future biochemical studies will explain the neuroserpin‐autophagy signalling network involvement in the retinal cells in glaucoma.