Müller cells are the major glia of the retina that serve numerous functions essential to retinal homeostasis, yet the contribution of Müller glial dysfunction to retinal diseases remains largely unknown. We have developed a transgenic model using a portion of the regulatory region of the retinaldehyde binding protein 1 gene for conditional Müller cell ablation and the consequences of primary Müller cell dysfunction have been studied in adult mice. We found that selective ablation of Müller cells led to photoreceptor apoptosis, vascular telangiectasis, blood-retinal barrier breakdown and, later, intraretinal neovascularization. These changes were accompanied by impaired retinal function and an imbalance between vascular endothelial growth factor-A (VEGF-A) and pigment epithelium derived factor. Intravitreal injection of cilliary neurotrophic factor inhibited photoreceptor injury but had no effect on the vasculopathy. Conversely, inhibition of VEGF-A activity attenuated vascular leak but did not protect photoreceptors. Our findings show that Müller glial deficiency may be an important upstream cause of retinal neuronal and vascular pathologies in retinal diseases. Combined neuroprotective and anti-angiogenic therapies may be required to treat Müller cell deficiency in retinal diseases and in other parts of the central nervous system associated with glial dysfunction.

Retinal vascular diseases collectively represent a leading cause of blindness. Unsurprisingly, pathological characterisation and treatment of retinal 'vascular' diseases have primarily focused on the aetiology and consequences of vascular dysfunction. Far less research has addressed the contribution of neuronal and glial dysfunction to the disease process of retinal vascular disorders. Ample evidence now suggests that retinal vasculopathy only uncommonly occurs in isolation, usually existing in concert with neuropathy and gliopathy. Retinal glia (Müller cells, astrocytes and microglia) have been reported to exhibit morphological and functional changes in both early and advanced phases of almost every retinal vascular disease. It is anticipated that identifying the causes of glial activation and dysfunction, and their contribution to loss of vision in retinal vascular disease, will lead to a better understanding of retinal vascular diseases, which might ultimately be translated into novel clinical therapies.

The human retina, which is part of the central nervous system, has exceptionally high energy demands that requires an efficient metabolism of glucose, lipids, and amino acids. Dysregulation of retinal metabolism disrupts local energy supply and redox balance, contributing to the pathogenesis of diverse retinal diseases, including age-related macular degeneration, diabetic retinopathy, inherited retinal degenerations, and Macular Telangiectasia. A better understanding of the contribution of dysregulated metabolism to retinal diseases may provide better therapeutic targets than we currently have.

We found that most patients with MacTel-2 possess retinal autoantibodies, the most prevalent of which were directed against AGL, RBP3, and CK-B. The localization of retinal proteins bound by AGL, RBP3, and CK-B autoantibodies is consistent with their putative physiological functions. These findings provide potentially novel mechanisms for the etiology and pathogenesis of MacTel-2.

These results further characterize expression of IL-6/gp130 cytokines and Jak-STAT signaling in outer retinal disease, suggesting Müller cells are critical for their induction and action. Lack of rLIF-mediated neuroprotection contrasts with other retinal degenerations where Müller cell integrity remains intact or photoreceptor apoptosis occurs in a more rapid, synchronous manner. The presence of Müller cells may be critical for the functional benefits of rLIF and potentially other IL-6/gp130 cytokines.

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Fast gating is a unique property of chloride channels, where a permeating Cl(-) ion acts as its own ligand in opening the channel. The glutamate residue implicated in fast gating normally carries a unit negative charge. Whether this charge needs to be protonated to enable permeation of a Cl(-) ion is an important question that will affect how models of chloride channels are constructed. We investigate the energetic consequences of the charge state of this glutamate residue from continuum electrostatics using a schematic cylindrical channel model. Both analytical solutions of the Poisson equation for an infinite cylinder and numerical ones for a finite cylinder are employed in the calculations.