Rod bipolar cells dysfunction occurs before ganglion cells loss in excitotoxin-damaged mouse retina

Yumeng Shen,Ying Shen,Xue Luo,Scott Nawy,Shiliang Liu,Yin Shen

doi:10.1038/s41419-019-2140-x

Abstract

Progressive degeneration of retinal ganglion cells (RGCs) will cause a blinding disease. Most of the study is focusing on the RGCs itself. In this study, we demonstrate a decline of the presynaptic rod bipolar cells (RBCs) response precedes RGCs loss and a decrease of protein kinase Cα (PKCα) protein expression in RBCs dendrites, using whole-cell voltage-clamp, electroretinography (ERG) measurements, immunostaining and co-immunoprecipitation. We present evidence showing that N-methyl D-aspartate receptor subtype 2B (NR2B)/protein interacting with C kinase 1 (PICK1)-dependent degradation of PKCα protein in RBCs contributes to RBCs functional loss. Mechanistically, NR2B forms a complex with PKCα and PICK1 to promote the degradation of PKCα in a phosphorylation- and proteasome-dependent manner. Similar deficits in PKCα expression and response sensitivity were observed in acute ocular hypertension and optic never crush models. In conclusion, we find that three separate experimental models of neurodegeneration, often used to specifically target RGCs, disrupt RBCs function prior to the loss of RGCs. Our findings provide useful information for developing new diagnostic tools and treatments for retinal ganglion cells degeneration disease.

Highlights

Retinal bipolar cells, receive light signal inputs from rods or cones, and send outputs to ganglion and amacrine cells[1]
In the optic nerve crush (ONC) model, which is a model of retinal ganglion cells (RGCs) degeneration that is unrelated to changes in intraocular pressure (IOP)[24], protein kinase Cα (PKCα) significantly decreased within 1–2 weeks (Fig. 1b)
Bipolar cells are interneuron whose axons do not project into the optic nerve, damage to this nerve none-the-less resulted in significant loss of PKCα

Summary

Introduction

Receive light signal inputs from rods or cones, and send outputs to ganglion and amacrine cells[1]. The ON pathway is mediated by rod bipolar cells (RBCs) which receive input exclusively from rods, and ON cone bipolar cells (ON-CBCs) which collect input from cones, both respond to light increments with membrane. Some key cellular regulators, such as PKCα have been shown to be expressed in RBCs, but not in ON CBCs4. Activation of PKCα induces a conformational change and translocation to the cell membrane[6]. PKCα regulates GABAergic feedback onto RBC terminal, reducing GABA-induced currents generated by the release of GABA from amacrine cells[7,8,9]. PKCα has been suggested to play an important role in the modulation of TRPM110–12, the transduction channel that mediates

Methods

Results

Conclusion