Gap junctions form bridges between bench studies and clinical ophthalmology

In retinal neurodegenerative disorders, the initial degeneration of primary target cells is frequently followed by a phenomenon known as the bystander effect, wherein neighboring, initially unaffected cells also undergo degeneration. This secondary cell death can exceed the number of directly insulted cells (Frantseva et al., 2002a,b; de Rivero Vaccari et al. 2007; Wang et al. 2010; Park et al. 2011; Akopian et al. 2014; O'Brien and Bloomfield, 2018). Although the precise mechanisms underlying the bystander effect remain incompletely understood, gap junctions (GJs) have been implicated in mediating the spread of pro-death signals from injured to adjacent cells. Consequently, GJs have become a focal point in recent research, with GJ blockade proposed as a neuroprotective strategy in progressive retinal diseases, such as diabetic retinopathy, ischemia, and glaucoma. However, GJs are essential in physiological neuronal communication, and their prolonged inhibition may disrupt visual processing (Bloomfield and Völgyi, 2009; Völgyi et al., 2013; O'Brien and Bloomfield, 2018), thereby limiting the therapeutic utility of GJ blockades in the treatment of chronic retinal conditions. Considering this, we propose an alternative hypothesis: rather than solely contributing to neurodegeneration, GJs may also support cell survival by facilitating the intercellular transmission of protective molecules (termed here as 'health-signals') that counteract apoptotic cascades and possibly attenuate the primary insult itself. In this framework, GJs could disseminate "health signals" across the retinal network, suggesting that co-administering neuroprotective agents with GJ permeability enhancers might amplify their therapeutic reach. While this hypothesis assumes that key endogenous molecules can cross GJs, their specific properties and transjunctional dynamics remain poorly understood. This review consolidates current knowledge on GJ-mediated communication and explores its clinical utility in retinal neuroprotection.