Glaucoma is the most common cause of irreversible blindness. Many patients with glaucoma suffer from elevated intraocular pressure (IOP), due to impaired drainage of aqueous humor fluid from the eye, and all current treatments are designed to lower IOP, implicating dysregulation of IOP as an important clinical problem. Because IOP is maintained within a narrow range over a lifetime in a healthy eye, it is thought that mechanically-driven feedback loops within the eye maintain IOP homeostasis, and in fact, good evidence for such loops now exists. Here we revisit the fluid mechanics of aqueous humor flow in the eye to estimate fluid shear stresses in relevant aqueous drainage tissues, in order to identify mechanical signals that may be involved in IOP homeostatic feedback loops. We find that shear stresses within the juxtacanalicular tissue are likely too small to play a significant role, except perhaps in the very immediate vicinity of the inner wall of Schlemm's canal. We estimate that the basement membrane underlying the inner wall of Schlemm's canal is exposed to very high shear stresses. Furthermore, we find remarkably large shear stresses acting on pores passing through the inner wall of Schlemm's canal. Finally, the inner wall of Schlemm's canal is exposed to moderate shear stresses that, unlike other locations in the outflow pathway, increase as IOP increases. Thus, the inner wall endothelial cells of Schlemm's canal are well-suited to participate in a shear stress-driven IOP homeostatic feedback loop.

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.