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Glutamatergic calcium dynamics and deregulation of rat retinal ganglion cells
Author(s) -
Hartwick Andrew T. E.,
Hamilton Claire M.,
Baldridge William H.
Publication year - 2008
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2008.154609
Subject(s) - kainate receptor , ampa receptor , nmda receptor , glutamate receptor , glutamatergic , neuroscience , excitatory postsynaptic potential , biology , cnqx , chemistry , retinal ganglion cell , retina , biochemistry , receptor , inhibitory postsynaptic potential
A rise in intracellular calcium levels ([Ca 2+ ] i ) is a key trigger for the lethal effects of the excitatory neurotransmitter glutamate in various central neurons, but a consensus has not been reached on the pathways that mediate glutamate‐dependent increases of [Ca 2+ ] i in retinal ganglion cells (RGCs). Using Ca 2+ imaging techniques we demonstrated that, in the absence of external Mg 2+ , the Ca 2+ signal evoked by glutamate was predominantly mediated by NMDA‐type glutamate receptors (NMDA‐Rs) in immunopanned RGCs isolated from neonatal or adult rats. Voltage‐gated Ca 2+ channels and AMPA/kainate‐Rs contributed a smaller portion of the Ca 2+ response at saturating concentrations of glutamate. Consistent with NMDA‐R involvement, extracellular Mg 2+ inhibited RGC glutamate responses, while glycine had a potentiating effect. With Mg 2+ present externally, the effect of AMPA/kainate‐R antagonists was enhanced and both NMDA‐ and AMPA/kainate‐R antagonists greatly reduced the glutamate‐induced increases of RGC [Ca 2+ ] i . This finding indicates that the primary contribution of AMPA/kainate‐Rs to RGC glutamatergic Ca 2+ dynamics is through the depolarization‐dependent relief of the Mg 2+ block of NMDA‐R channels. The effect of glutamate receptor antagonists on glutamatergic Ca 2+ signals from RGCs in adult rat retinal wholemounts yielded results similar to those obtained using immunopanned RGCs. Additional experiments on isolated RGCs revealed that during a 1 h glutamate (10–1000 μ m ) exposure, 18–28% of RGCs exhibited delayed Ca 2+ deregulation (DCD) and the RGCs that underwent DCD were positive for the death marker annexin V. RGCs with larger glutamate‐evoked Ca 2+ signals were more likely to undergo DCD, and NMDA‐R blockade significantly reduced the occurrence of DCD. Identifying the mechanisms underlying RGC excitotoxicity aids in our understanding of the pathophysiology of retinal ischaemia, and this work establishes a major role for NMDA‐R‐mediated increases in [Ca 2+ ] i in glutamate‐related RGC death.