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

• Published in: The European journal of neuroscience Vol. 35; no. 1; pp. 56 - 65
• Main Authors: Daniels, Bryan A., Wood, Leah, Tremblay, François, Baldridge, William H.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.01.2012
• Subjects: Adamantane - analogs & derivatives; Adamantane - metabolism; alpha -Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; alpha -Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; Animals; Calcium; Calcium - metabolism; Calcium permeability; Central nervous system; D-Amino-acid oxidase; D-Serine; fura-2; Glutamic acid receptors; Glutamic acid receptors (ionotropic); guinea pig; Guinea Pigs; Kainic Acid - pharmacology; Kainic acid receptors; multi-electrode array; N-Methyl-D-aspartic acid receptors; Nervous system; Neurons; Patch-Clamp Techniques; rat; Rats; Rats, Long-Evans; Receptors, AMPA - antagonists & inhibitors; Receptors, AMPA - metabolism; Receptors, Kainic Acid - antagonists & inhibitors; Receptors, Kainic Acid - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Retina; Retinal ganglion cells; Retinal Neurons - cytology; Retinal Neurons - drug effects; Retinal Neurons - metabolism; Serine - metabolism
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/j.1460-9568.2011.07925.x

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. D‐Serine is an important signaling molecule throughout the central nervous system, acting as an N‐methyl‐D‐aspartate receptor coagonist. This study investigated the D‐serine modulation of non‐N‐methyl‐D‐aspartate ionotropic glutamate receptors expressed by inner retinal neurons.