Intrinsically photosensitive retinal ganglion cells: Context-Dependent resilience and vulnerability

Retinal ganglion cells (RGCs) exhibit marked heterogeneity in their susceptibility to injury and disease. Intrinsically photosensitive retinal ganglion cells (ipRGCs), a small subset of melanopsin-expressing RGCs involved in non-image-forming visual functions, have emerged as a particularly informative example. In multiple experimental models, ipRGCs show relative resistance to acute insults such as optic nerve injury, excitotoxicity, and mitochondrial dysfuinction. In contrast, functional alterations and degeneration have been reported in aging and in neurodegenerative conditions including Alzheimer's and Parkinson's disease. This apparent discrepancy suggests that ipRGC survival may depend on the nature and duration of the underlying stress. In this review, we summarize current evidence on ipRGC resilience and vulnerability across a range of experimental and pathological contexts. We discuss candidate mechanisms that may contribute to these responses, including sustained activity, calcium handling, metabolic specialization, neurochemical interactions, and gene expression programs. We also consider the role of subtype-specific diversity within the ipRGC population in shaping these outcomes. Finally, we examine the potential of ipRGCs as biomarkers of disease and as a source of insight for neuroprotective strategies. Together, these observations support the view that ipRGC behaviour reflects an interaction between intrinsic cellular properties and the context in which they are engaged.