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Functional evidence for D-serine inhibition of non-N-methyl-D-aspartate ionotropic glutamate receptors in retinal neurons

Authors

  • Bryan A. Daniels,

    1. Department of Anatomy and Neurobiology, Dalhousie University, Sir Charles Tupper Building, 5850 College Street, Halifax, NS, Canada B3H 4R2
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    • Present address: Department of Pharmacology and Therapeutics, McGill University, 3649 Promenade Sir-William-Osler, Montreal, Quebec, Canada. H3G 0B1

  • Leah Wood,

    1. Department of Physiology and Biophysics, Dalhousie University, Sir Charles Tupper Building, 5850 College Street, Halifax, NS, Canada B3H 4R2
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  • François Tremblay,

    1. Department of Physiology and Biophysics, Dalhousie University, Sir Charles Tupper Building, 5850 College Street, Halifax, NS, Canada B3H 4R2
    2. Department of Ophthalmology and Visual Sciences, Laboratory for Retina and Optic Nerve Research, Dalhousie University, Sir Charles Tupper Building, 5850 College Street, Halifax, NS, Canada B3H 4R2
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  • William H. Baldridge

    1. Department of Anatomy and Neurobiology, Dalhousie University, Sir Charles Tupper Building, 5850 College Street, Halifax, NS, Canada B3H 4R2
    2. Department of Ophthalmology and Visual Sciences, Laboratory for Retina and Optic Nerve Research, Dalhousie University, Sir Charles Tupper Building, 5850 College Street, Halifax, NS, Canada B3H 4R2
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William H. Baldridge, 1Department of Anatomy and Neurobiology, as above.
E-mail: wbaldrid@dal.ca

Abstract

D-Serine is an important signaling molecule throughout the central nervous system, acting as an N-methyl-D-aspartate (NMDA) receptor coagonist. This study investigated the D-serine modulation of non-NMDA ionotropic glutamate receptors expressed by inner retinal neurons. We first identified that the degradation of endogenous retinal D-serine, by application of D-amino acid oxidase, caused an enhancement of kainate- and α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor-mediated calcium responses from the ganglion cell layer of the isolated rat retina and light-evoked responses obtained by multi-electrode array recordings from the guinea pig retina. Approximately 30–45% of cells were endogenously inhibited by D-serine, as suggested by the effect of D-amino acid oxidase. Conversely, bath application of D-serine caused a reduction in multi-electrode array recorded responses and decreased kainate, but not potassium-induced calcium responses, in a concentration-dependent manner (IC50, 280 μm). Using cultured retinal ganglion cells to reduce network influences, D-serine reduced kainate-induced calcium responses and AMPA induced whole-cell currents. Finally, the inhibitory effect of D-serine on the kainate-induced calcium response was abolished by IEM 1460, thereby identifying calcium-permeable AMPA receptors as a potential target for D-serine. To our knowledge, this is the first study to address specifically the effect of D-serine on AMPA/kainate receptors in intact central nervous system tissue, to identify its effect on calcium permeable AMPA receptors and to report the endogenous inhibition of AMPA/kainate receptors.

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