Abstract
Excitotoxicity has been implicated in the retinal neuronal loss in several ocular pathologies including glaucoma. Dysfunction of Excitatory Amino Acid Transporters is often a key component of the cascade leading to excitotoxic cell death. In the retina, glutamate transport is mainly operated by the glial glutamate transporter GLAST and the neuronal transporter GLT-1. In this study we evaluated the expression of GLAST and GLT-1 in a rat model of acute glaucoma based on the transient increase of intraocular pressure (IOP) and characterized by high glutamate levels during the reperfusion that follows the ischemic event associated with raised IOP. No changes were reported in GLAST expression while, at neuronal level, a reduction of glutamate uptake and of transporter reversal-mediated glutamate release was observed in isolated retinal synaptosomes. This was accompanied by modulation of GLT-1 expression leading to the reduction of the canonical 65 kDa form and upregulation of a GLT-1-related 38 kDa protein. These results support a role for neuronal transporters in glutamate accumulation observed in the retina following an ischemic event and suggest the presence of a GLT-1 neuronal new alternative splice variant, induced in response to the detrimental stimulus.
Highlights
L-glutamate is the major excitatory neurotransmitter in the Central Nervous System including the retina, where it is released by photoreceptors, bipolar and ganglion cells [1,2] and is responsible for the transmission of the light signal
Elevation of extracellular glutamate is a key factor in retinal neurodegeneration occurring in glaucoma and other retinal pathologies characterized by ischemic events [12,13,38,39]
We studied the modulation of two out of five Excitatory Amino Acid Transporters (EAATs) present in the retina, i.e. GLAST and GLT-1 during retinal ischemia/reperfusion, showing a decrease of neuronal glutamate uptake associated with a significant modulation of GLT-1 while no significant changes of GLAST expression were evident
Summary
L-glutamate is the major excitatory neurotransmitter in the Central Nervous System including the retina, where it is released by photoreceptors, bipolar and ganglion cells [1,2] and is responsible for the transmission of the light signal. Many experimental evidence suggest that excitotoxicity is one of the main factors involved in ganglion cell death observed during retinal hypoxic/ischemic events [11,12,13,14] which are common in several ocular pathologies including diabetic retinopathy, retinal and choroidal vessels occlusion and glaucoma [15,16,17]. This hypothesis is strongly supported by the neuroprotection afforded by intravitreal or systemic treatment with NMDA and nonNMDA receptor antagonists [11,13,18,19] or by the open channel blocker memantine [20,21] in acute and chronic models of retinal ganglion cells (RGCs) death
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