Abstract
D-amino acid oxidase (DAO) degrades D-serine, a co-agonist at the NMDA receptor (NMDAR). Hypofunction of the NMDAR has been suggested to contribute to the pathophysiology of schizophrenia. Intriguingly, DAO has been recently identified as a risk factor for schizophrenia through genetic association studies. A naturally occurring mouse strain (ddY/DAO-) has been identified which lacks DAO activity. We have characterized this strain both behaviorally and biochemically to evaluate DAO as a target for schizophrenia. We have confirmed that this strain lacks DAO activity and shown for the first time it has increased occupancy of the NMDAR glycine site due to elevated extracellular D-serine levels and has enhanced NMDAR function in vivo. Furthermore, the ddY/DAO- strain displays behaviors which suggest that it will be a useful tool for evaluation of the clinical benefit of DAO inhibition in schizophrenia.
MeSH terms
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Acoustic Stimulation / methods
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Animals
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Brain Chemistry / drug effects
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Brain Chemistry / genetics*
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Cyclic GMP / metabolism
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D-Amino-Acid Oxidase / deficiency*
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Disease Models, Animal
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Dose-Response Relationship, Radiation
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Excitatory Amino Acid Antagonists / pharmacology
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Extremities / physiology
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Female
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Male
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Mice
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Mice, Inbred Strains
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Mice, Knockout / physiology*
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Motor Activity / drug effects
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Motor Activity / genetics
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Neural Inhibition / genetics
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Neurologic Examination / methods
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Phencyclidine / administration & dosage
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Psychomotor Performance / drug effects
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Psychomotor Performance / physiology
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Quinolones / pharmacology
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Reaction Time / genetics
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Reflex, Startle / genetics
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Schizophrenia / metabolism
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Schizophrenia / physiopathology*
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Sex Factors
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Swimming / physiology
Substances
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Excitatory Amino Acid Antagonists
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Quinolones
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Dao1 protein, mouse
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D-Amino-Acid Oxidase
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Cyclic GMP
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L 701324
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Phencyclidine