Retinal NMDA receptor function and expression are altered in a mouse lacking D-amino acid oxidase.
D-serine is present in the vertebrate retina and serves as a coagonist for the N-methyl-D-aspartate (NMDA) receptors of ganglion cells. Although the enzyme D-amino acid oxidase (DAO) has been implicated as a pathway for d-serine degradation, its role in the retina has not been established. In this study, we investigated the role of DAO in regulating D-serine levels using a mutant mouse line deficient in DAO (ddY/DAO(-)) and compared these results with their wild-type counterparts (ddY/DAO(+)). Our results show that DAO is functionally present in the mouse retina and normally serves to reduce the background levels of D-serine. The enzymatic activity of DAO was restricted to the inner plexiform layer as determined by histochemical analysis. Using capillary electrophoresis, we showed that mutant mice had much higher levels of D-serine. Whole cell recordings from identified retinal ganglion cells demonstrated that DAO-deficient animals had light-evoked synaptic activity strongly biased toward a high NMDA-to-AMPA receptor ratio. In contrast, recordings from wild-type ganglion cells showed a more balanced ratio between the two receptor subclasses. Immunostaining for AMPA and NMDA receptors was carried out to compare the two receptor ratios by quantitative immunofluorescence. These studies revealed that the mutant mouse had a significantly higher representation of NMDA receptors compared with the wild-type controls. We conclude that 1) DAO is an important regulatory enzyme and normally functions to reduce D-serine levels in the retina, and 2) D-serine levels play a role in the expression of NMDA receptors and the NMDA-to-AMPA receptor ratio.
Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota;
Eric C
EC
Gustafson
Catherine W
CW
Morgans
Merve
M
Tekmen
Steven J
SJ
Sullivan
Manuel
M
Esguerra
Ryuichi
R
Konno
Robert F
RF
Miller
D000200:Action Potentials; D000818:Animals; D003605:D-Amino-Acid Oxidase / Q000172:deficiency / Q000235:genetics*; D019706:Excitatory Postsynaptic Potentials; D051379:Mice; D009154:Mutation; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000502:physiology; D012694:Serine / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism
D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; C485958:Dao1 protein, mouse; D003605:D-Amino-Acid Oxidase
d-amino acid oxidase; d-serine; glutamate receptors; mouse; retinal ganglion cells