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The Journal of Neuroscience, February 4, 2009, 29(5):1469-1479; doi:10.1523/JNEUROSCI.4240-08.2009

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Cellular/Molecular
Coagonist Release Modulates NMDA Receptor Subtype Contributions at Synaptic Inputs to Retinal Ganglion Cells

Trisha L. Kalbaugh, Jun Zhang, and Jeffrey S. Diamond

Synaptic Physiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-3701

Correspondence should be addressed to Dr. Jeffrey S. Diamond, Synaptic Physiology Section, National Institute of Neurological Disorders and Stroke/National Institutes of Health, 35 Convent Drive, Building 35, Room 3C-1000, Bethesda, MD 20892-3701. Email: diamondj{at}ninds.nih.gov

NMDA receptors (NMDARs) are tetrameric protein complexes usually comprising two NR1 and two NR2 subunits. Different combinations of four potential NR2 subunits (NR2A-D) confer diversity in developmental expression, subsynaptic localization, and functional characteristics, including affinity for neurotransmitter. NR2B-containing NMDARs, for example, exhibit relatively high affinity both for glutamate and the coagonist glycine. Although multiple NMDAR subtypes can colocalize at individual synapses, particular subtypes often mediate inputs from distinct functional pathways. In retinal ganglion cells (RGCs), NMDARs contribute to synaptic responses elicited by light stimulus onset ("ON") and offset ("OFF"), but roles for particular NMDAR subtypes, and potential segregation between the ON and OFF pathways, have not been explored. Moreover, elements in the retinal circuitry release two different NMDAR coagonists, glycine and D-serine, but the effects of endogenous coagonist release on the relative contribution of different NMDAR subtypes are unclear. Here, we show that coagonist release within the retina modulates the relative contribution of different NMDARs in the ON pathway of the rat retina. By pharmacologically stimulating functional pathways independently in acute slices and recording synaptic responses in RGCs, we show that ON inputs, but not OFF inputs, are mediated in part by NMDARs exhibiting NR2B-like pharmacology. Furthermore, suppressing release of NMDAR coagonist reduces NMDAR activation at ON synapses and increases the relative contribution of these putative NR2B-containing receptors. These results demonstrate direct evidence for evoked coagonist release onto NMDARs and indicate that modulating coagonist release may regulate the relative activation of different NMDAR subtypes in the ON pathway.

Key words: NMDA receptor; AMPA receptor; glycine; retinal ganglion cell; retinal bipolar cell; synaptic transmission; retina

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Received Sept. 2, 2008; revised Dec. 31, 2008; accepted Jan. 2, 2009.

Correspondence should be addressed to Dr. Jeffrey S. Diamond, Synaptic Physiology Section, National Institute of Neurological Disorders and Stroke/National Institutes of Health, 35 Convent Drive, Building 35, Room 3C-1000, Bethesda, MD 20892-3701. Email: diamondj{at}ninds.nih.gov

This article has been cited by other articles:

				J. Zhang and J. S. Diamond Subunit- and Pathway-Specific Localization of NMDA Receptors and Scaffolding Proteins at Ganglion Cell Synapses in Rat Retina J. Neurosci., April 1, 2009; 29(13): 4274 - 4286. [Abstract] [Full Text] [PDF]

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