Behavioral and biochemical characterization of a mutant mouse strain lacking D-amino acid oxidase activity and its implications for schizophrenia.
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.
Almond
S L
SL
Merck Sharp and Dohme, Neuroscience Research Centre, Harlow, Essex, CM20 2QR, UK.
Fradley
R L
RL
Armstrong
E J
EJ
Heavens
R B
RB
Rutter
A R
AR
Newman
R J
RJ
Chiu
C S
CS
Konno
R
R
Hutson
P H
PH
Brandon
N J
NJ
D000161:Acoustic Stimulation / Q000379:methods; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics*; D006152:Cyclic GMP / Q000378:metabolism; D003605:D-Amino-Acid Oxidase / Q000172:deficiency*; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005121:Extremities / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout / Q000502:physiology*; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009433:Neural Inhibition / Q000235:genetics; D009460:Neurologic Examination / Q000379:methods; D010622:Phencyclidine / Q000008:administration & dosage; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D015363:Quinolones / Q000494:pharmacology; D011930:Reaction Time / Q000235:genetics; D013216:Reflex, Startle / Q000235:genetics; D012559:Schizophrenia / Q000378:metabolism / Q000503:physiopathology*; D012737:Sex Factors; D013550:Swimming / Q000502:physiology
D018691:Excitatory Amino Acid Antagonists; D015363:Quinolones; C485958:Dao1 protein, mouse; D003605:D-Amino-Acid Oxidase; D006152:Cyclic GMP; C094635:L 701324; D010622:Phencyclidine