Modulating retinal glutamate transport in health and disease.
The interruption of an adequate blood supply to tissue in the nervous system, as can occur by thrombotic embolism or stroke, leads to "ischaemic" injury and permanent neuronal damage. A number of conditions can cause retinal ischaemia, including central retinal artery occlusion, vein occlusion and carotid artery disease. These serious conditions often result in blindness. Moreover, the pathogenesis of glaucoma, which affects over 3 million people and is the second most common cause of blindness in the world (WHO World Health Report 1999), is now recognised as an ischaemic injury.
In order to develop a clinical strategy to manage ischaemic disease successfully, a greater understanding is needed of the complex processes which underlie ischaemic neuronal pathology and dysfunction. It is apparent that the excitatory amino acid, glutamate, plays a pivotal role in the development of ischaemic tissue damage. During an ischaemic event, extracellular levels of glutamate rise and trigger a cascade of events which ultimately result in neuronal death. Thus the regulation of extracellular glutamate levels under physiological and pathophysiological conditions is a prerequisite for the prevention of neurodegeneration.
My current interest is to elucidate the mechanisms by which extracellular glutamate concentrations are maintained by the glutamate transporter proteins located on retinal cells. Four distinct glutamate transporters have been identified in the rat retina. These proteins transport glutamate between the extracellular space, neurones and glial cells. The activity of these transporters is altered during an ischaemic episode. In particular, the activity of the glial glutamate transporter, GLAST, is suppressed. Thus, the hypothesis upon which this project is based is that the stimulation of GLAST activity will prevent the catastrophic rise in extracellular glutamate concentration that occurs during ischaemia. Recent evidence suggests that the activity of glutamate transporters can be modulated by protein kinase C (PKC).