Synaptic control of retinal ganglion cell survival and axon regeneration

Injury to retinal ganglion cell (RGC) axons in neurodegenerative conditions like glaucoma leads to irreversible vision loss. A major therapeutic challenge is promoting RGC survival and axon regeneration. Canonical research focused on intrinsic neuronal growth capacity and the inhibitory central nervous system (CNS) environment, but overlooking the role of retinal synaptic communication. This review summarizes emerging evidence that retinal interneuron-to-RGC synaptic connections are both structurally and molecularly dysregulated following RGC axon injury. Such synaptic plasticity critically regulates RGC survival and regenerative capacity, at least partly by orchestrating intrinsic repair programs. We then address two central unresolved questions: first, what are the specific molecular pathways that alter this interneuron-to-RGC signaling after injury, and second, how do glial cells participate in this transsynaptic dysregulation. Finally, we evaluate the translational potential of these findings, including the identification of biomarkers and the development of novel neuroprotective strategies that target synaptic connections. Synaptic communication is a fundamental regulator of RGC fate after injury. Understanding synaptic dysregulation and the mechanisms involved is essential for developing new synapse-targeted strategies to monitor progression of neurodegenerative diseases and promote neural repair.