Regulation of metabolism and distribution of gamma-aminobutyric acid in the rat retina

Abstract

{dollar}\gamma{dollar}-Aminobutyric acid (GABA), an inhibitory neurotransmitter, and the enzyme catalyzing its synthesis, glutamic acid decarboxylase (GAD), occur in most mammalian retinae only within a subset of amacrine neurons. GABA-transaminase (GABA-T), the catabolic enzyme for GABA, is more widely distributed in the retina. The role played by GABA in retinal visual processing is not well understood. We employed gabaculine and {dollar}\gamma{dollar}-vinyl GABA, specific enzyme-activated irreversible inhibitors of GABA-T, and {dollar}\gamma{dollar}-acetylenic GABA, which inactivates both GAD and GABA-T, to study that role.;Our initial studies focussed on the action of those inhibitors in the retina, first on the activities of GAD and GABA-T, and then on the levels of GABA itself. Upon subcutaneous administration each inactivated its target enzymes more potently in the retina than in several other brain regions, producing large and long-lasting increases in levels of retinal GABA. Immunocytochemical studies showed that GABA accumulated largely in Muller glial cells after inactivation of GABA-T, providing direct evidence that these cells participate in the uptake and degradation of GABA in vivo. We then used gabaculine to study the effect of light on the retinal synthesis of GABA. Light appeared to stimulate synthesis of GABA, because more GABA accumulated in retinae of gabaculine-treated rats held in the light than in those of rats placed in darkness. 2-Amino-4-phosphonobutyrate (APB) is a glutamate receptor agonist that selectively suppresses the light response of on-depolarizing bipolar cells (ODBCs). APB diminished the post-gabaculine accumulation of retinal GABA in rats held in the light but not in those placed in darkness, suggesting that the light-dependent increase in retinal synthesis of GABA occurred in response to the activity of ODBCs. Our results support the hypothesis that GABAergic amacrine neurons receive excitatory input from ODBCs. This suggest a specific manner in which GABA-mediated inhibition in the inner retina could contribute to the receptive field properties of retinal ganglion cells.