Crosstalk Between Neuronal and Glial Cells in Diabetic Retinopathy: Mechanisms and Implications for Neurodegeneration

Diabetic retinopathy (DR) has traditionally been classified as a microvascular disorder; however, emerging evidence underscores its profound impact on retinal neurodegeneration, which often precedes detectable vascular pathology. This paradigm shift positions DR as a neurovascular disease, where neuronal dysfunction and glial reactivity play critical roles in early disease progression. While retinal neurodegeneration is a hallmark of early DR, the underlying mechanisms remain poorly understood. Given the essential trophic, structural, and metabolic support provided by glial cells to neurons, dysregulated neuron-glia interactions may be a key driver of neurodegeneration in DR. The retina comprises a highly organized network of neuronal and glial cells that communicate via intricate signaling pathways, mediated by cytokines, growth factors, and metabolic intermediates. Each glial cell type, i.e., astrocytes, Müller cells, and microglia exhibit distinct structural and functional properties, determining their unique crosstalk with retinal neurons. Disruptions in these interactions can exacerbate neuroinflammatory and excitotoxic insults, contributing to neuronal apoptosis and synaptic dysfunction. This review explores the dynamic interplay between retinal glial and neuronal cells in the context of DR, emphasizing how glial dysregulation may accelerate neurodegeneration. By elucidating these mechanisms, we aim to identify potential therapeutic targets that could mitigate early neuroglial damage in diabetic retinopathy.