Glutamate and neurodegeneration in the retina

Abstract

L-Glutamate is a neurotransmitter throughout the various levels of retinal neurons (photoreceptors, bipolar cells, ganglion cells) and acts at a range of ionotropic (iGlu) and metabotropic glutamate (mGlu) receptors to exert its physiological roles. A function unique to the retina can be ascribed to mGlu6 receptors, which are expressed only by ON bipolar cells at the sign-inverting synapse formed by photoreceptors. More conventional excitatory sign- conserving synapses utilizing iGlu receptors are formed at other locations in the retina. Over-activation of iGlu receptors (and especially NMDA receptors) is known to lead to excitotoxicity in the retina, as in other areas of the nervous system, and this may be associated with excessive neuronal Ca2+ influx. This excitotoxicity can be prevented or countered by iGlu receptor antagonists, both in vitro and in vivo. Furthermore, in some experimental models of retinal neurodegeneration, e.g., for glaucoma or ischemia, a number of different types of iGluR antagonists have been shown to be effective in a variety of species. In particular, the uncompetitive NMDA antagonist memantine has shown promise in experimental studies, but clinical trials to treat glaucoma with this drug have not had a successful outcome, possibly due to the unavailability of suitable markers of disease progression and heterogeneity of the disease in humans. It is thus important that further work is carried out so as to translate preclinical findings on neurodegeneration into successful clinical treatments.