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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 586/14/3425    most recent jphysiol.2008.154609v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Hartwick, A. T. E. Articles by Baldridge, W. H. PubMed PubMed Citation Articles by Hartwick, A. T. E. Articles by Baldridge, W. H. Related Collections Neuroscience

¹ Retina and Optic Nerve Research Laboratory and the Departments of
² Anatomy & Neurobiology
³ Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada

A rise in intracellular calcium levels ([Ca²⁺]_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 [Ca²⁺]_i in retinal ganglion cells (RGCs). Using Ca²⁺ imaging techniques we demonstrated that, in the absence of external Mg²⁺, the Ca²⁺ 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 Ca²⁺ channels and AMPA/kainate-Rs contributed a smaller portion of the Ca²⁺ response at saturating concentrations of glutamate. Consistent with NMDA-R involvement, extracellular Mg²⁺ inhibited RGC glutamate responses, while glycine had a potentiating effect. With Mg²⁺ 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 [Ca²⁺]_i. This finding indicates that the primary contribution of AMPA/kainate-Rs to RGC glutamatergic Ca²⁺ dynamics is through the depolarization-dependent relief of the Mg²⁺ block of NMDA-R channels. The effect of glutamate receptor antagonists on glutamatergic Ca²⁺ 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 µM) exposure, 18–28% of RGCs exhibited delayed Ca²⁺ deregulation (DCD) and the RGCs that underwent DCD were positive for the death marker annexin V. RGCs with larger glutamate-evoked Ca²⁺ 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 [Ca²⁺]_i in glutamate-related RGC death.

(Received 8 April 2008; accepted after revision 14 May 2008; first published online 15 May 2008)
Corresponding author W. H. Baldridge: Department of Anatomy & Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 1X5. Email: wbaldrid{at}dal.ca