Modulation of Presynaptic Inhibitory Retinal Circuits for Retinal Ganglion Cell Neuroprotection in Glaucoma

ABSTRACT Glaucoma is a leading cause of irreversible blindness, yet the circuit‐level mechanisms contributing to retinal ganglion cell (RGC) degeneration remain incompletely defined. Although multiple neuroprotective strategies have been explored, clinical translation remains limited. Here, we identify early dysfunction of inner retinal inhibitory circuitry as a modifiable contributor to RGC vulnerability during ocular hypertensive stress. In mouse ocular hypertension models, inner nuclear layer neurons exhibited increased c‐fos expression and enhanced oscillatory potential‐associated differential electroretinography signals before substantial RGC loss was detected, suggesting early retinal circuit hyperactivity. Broad pharmacological attenuation of GABAergic and glycinergic inhibitory signaling improved RGC survival without reducing intraocular pressure, supporting a functional contribution of inhibitory neurotransmission to RGC vulnerability. Moreover, Cre‐dependent AAV delivery of Lin28, an RNA‐binding regulator of post‐transcriptional gene expression, to Vgat‐positive inhibitory interneurons increased RGC survival compared with Vgat‐EGFP controls and Vglut2‐lineage Lin28 expression. Vgat‐targeted Lin28 also reduced c‐fos expression and oscillatory potential‐associated differential electroretinogram abnormalities, indicating suppression of ocular hypertension‐associated inner retinal hyperactivity. In addition, ocular hypertension was associated with altered sleep architecture, and Vgat‐targeted Lin28 expression was associated with mitigation of these alterations. These findings position presynaptic inhibitory retinal circuitry as an early and modifiable contributor to glaucomatous RGC vulnerability.