PTEN Expression Regulates Gap Junction Connectivity in the Retina.

Ashley M Chen,Alexander Harris,Nicholas C Brecha,Luis Pérez de Sevilla Müller,Shaghauyegh S Azar

doi:10.3389/fnana.2021.629244

Abstract

Manipulation of the phosphatase and tensin homolog (PTEN) pathway has been suggested as a therapeutic approach to treat or prevent vision loss due to retinal disease. In this study, we investigated the effects of deleting one copy of Pten in a well-characterized class of retinal ganglion cells called α-ganglion cells in the mouse retina. In Pten+/– retinas, α-ganglion cells did not exhibit major changes in their dendritic structure, although most cells developed a few, unusual loop-forming dendrites. By contrast, α-ganglion cells exhibited a significant decrease in heterologous and homologous gap junction mediated cell coupling with other retinal ganglion and amacrine cells. Additionally, the majority of OFF α-ganglion cells (12/18 cells) formed novel coupling to displaced amacrine cells. The number of connexin36 puncta, the predominant connexin that mediates gap junction communication at electrical synapses, was decreased by at least 50% on OFF α-ganglion cells. Reduced and incorrect gap junction connectivity of α-ganglion cells will affect their functional properties and alter visual image processing in the retina. The anomalous connectivity of retinal ganglion cells would potentially limit future therapeutic approaches involving manipulation of the Pten pathway for treating ganglion cell degeneration in diseases like glaucoma, traumatic brain injury, Parkinson’s, and Alzheimer’s diseases.

Highlights

The phosphatase and tensin homolog deleted on chromosome ten (Pten) protein is a potential molecular target for novel therapeutic strategies to treat optic neuropathies (Guzman-Aranguez et al, 2013; Ogino et al, 2016)
Characterization of the Ganglion Cell Layer in the PV-Pten+/- Mouse Retina In PV-Pten+/+ and PV-Pten+/− retinas, tdTomato fluorescence was found in retinal neurons. tdTomato fluorescence (Figures 1A,B) was observed in the somata, dendrites, and axons, with the strongest expression in the soma
TdTomato fluorescence was observed in somata in the inner nuclear layer (INL) adjacent to the inner plexiform layer (IPL) in PV-Pten+/+ and PV-Pten+/− retinas

Summary

Introduction

The phosphatase and tensin homolog deleted on chromosome ten (Pten) protein is a potential molecular target for novel therapeutic strategies to treat optic neuropathies (Guzman-Aranguez et al, 2013; Ogino et al, 2016). PTEN Expression Regulates Gap Junctions communication between glia cells (González-Sánchez et al, 2016), perhaps due to Pten’s effect on protein kinases (Preiss et al, 2007), which mediate phosphorylation of connexins (Xia and Mills, 2004; Urschel et al, 2006; Pérez de Sevilla Müller et al, 2010a). Gap junctions are intercellular channels formed by connexins between retinal neurons that influence the propagation and integration of visual signals (Bloomfield and Völgyi, 2009). Gap junctions are reported to participate in neuronal spike synchrony to enhance the saliency of visual signals, and mediate changes in light adaptation and circadian rhythms (Söhl et al, 2005; Hartveit and Veruki, 2012; Völgyi et al, 2013a; O’Brien, 2014). Blockade of Cx36 gap junctions provides RGC protection in glaucoma models (Akopian et al, 2014, 2016; Chen et al, 2015)

Methods

Results

Discussion

Conclusion