Metabolic regulation of visual acuity.

Abstract

Photoreceptors signal ON and OFF pathways via a synapse with bipolar cells that are transmitted to retinal ganglion cells (RGCs) for luminance and contrast detection. Retinal neurons metabolize glucose whose transport is mediated by photoreceptor contact with the adjacent retinal pigment epithelium (RPE). Rod loss in retinitis pigmentosa (RP) reduces RPE contact, diminishing glucose transport. We show diminished glucose leads to light hyperresponsiveness driven by deregulated ON cone bipolar signaling. Transmission of this constitutive signal to RGCs causes ON > OFF signaling imbalance and failure to detect luminance and contrast changes. Our results suggest that the aspartate-malate shuttle in GABAergic amacrine cells metabolizes glucose to γ-aminobutyric acid (GABA), which in turn regulates the ON cone bipolar signal. GABA_A receptor agonists such as Ativan are a widely prescribed first-line therapy for seizures initiated by low brain GABA, and we show that Ativan restores ON cone bipolar cell regulation in RP where retinal GABA is diminished, reestablishing luminance and contrast detection.