Diabetes changes ionotropic glutamate receptor subunit expression level in the human retina

Abstract

Early diabetic retinopathy is characterized by changes in subtle visual functions such as contrast sensitivity and dark adaptation. The outcome of several studies suggests that glutamate is involved in retinal neurodegeneration during diabetes. We hypothesized that the protein levels of ionotropic glutamate receptor subunits are altered in the retina during diabetes. Therefore, we investigated whether human diabetic patients have altered immunoreactivity of ionotropic glutamate receptor subunits in the retina. In total, 12 donor eyes from subjects with diabetes mellitus were examined and compared to 6 eyes from non-diabetic subjects without known ocular disease, serving as controls. Immunohistochemical analysis was performed using specific antibodies directed against the ionotropic α-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptor subunits GluR1, GluR2, GluR4, and against the N-methyl-D-aspartate glutamate receptor subunit NR1. In the inner plexiform and outer plexiform layers the immunoreactivity of GluR2 and NR1 subunits was significantly increased in subjects with diabetes when compared to the levels found in controls. No significant changes in GluR1 and GluR4 subunit expression were observed.These results suggest that early visual dysfunction in diabetic patients may be due, at least partially, to changes in glutamate receptor subunit expression or distribution. IntroductionDiabetic retinopathy (DR) is a leading cause of blindness in working-age adults in developed countries. The vascular changes that occur in DR are well documented, and include loss of pericytes and endothelial cells, the formation of microaneurysms, basement membrane thickening and blood-retinal barrier breakdown (Cai and Boulton, 2002). In addition to the vascular

Early Visual Deficits in Streptozotocin-Induced Diabetic Long Evans Rats

“…From a molecular biology standpoint, diabetes has been shown to alter the levels and receptors of several inner retinal neurotransmitters (most notably dopamine and gamma-aminobutyric acid [GABA]), as early as 4 weeks post-STZ. 30,51,52 Cellularly, increased cell death of amacrine and ganglion cells has been observed within weeks of STZ injection. 28,33 Functionally, other ERG studies have reported dysfunction in amacrine-and ganglion cell-dominated OPs and scotopic threshold response (STR) at 4 weeks post-STZ.…”

Neurodegeneration is an early event in diabetic retinopathy: therapeutic implications

“…These elevated concentrations of extracellular and synaptic glutamate in the retina lead to the so-called ‘excitotoxicity’ in which the excess of glutamate stimulation causes an uncontrolled intracellular calcium response in postsynaptic neurons that results in cell death 50. The excitoxicity of glutamate is the result of overactivation of ionotropic glutamate receptors, mainly α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) and N-methyl- d -aspartame (NMDA), which have been found to be overexpressed in streptozotocin-induced diabetic rats 52 53. There are at least two mechanisms involved in glutamate-induced apoptosis: a caspase-3-dependent pathway and a caspase-independent pathway involving calpain and mitochondrial apoptosis-inducing factor 54…”

The Significance of Vascular and Neural Apoptosis to the Pathology of Diabetic Retinopathy

“…The results showed that the immunoreactivity of GluR2 and NR1 subunits was significantly increased by diabetes. 61 Studies in diabetic rats also indicated that immunoreactivity of AMPA and NMDA receptor subunits Glu2/3 and NMDA1 were increased. 62 In addition, one of these studies indicated that AMPA receptor subunit GluR2 phosphorylation and cellular distribution were altered during the early stages of diabetes, perhaps reflecting a shift in receptor recycling.…”