Increasing evidence points to a role for dysfunctional
glutamate N-methyl-D-aspartate receptor (NMDAR) neurotransmission in
schizophrenia.
D-aspartate is an atypical
amino acid that activates NMDARs through binding to the
glutamate site on GluN2 subunits.
D-aspartate is present in high amounts in the embryonic brain of mammals and rapidly decreases after birth, due to the activity of the
enzyme D-aspartate oxidase (DDO). The agonistic activity exerted by
D-aspartate on NMDARs and its neurodevelopmental occurrence make this D-
amino acid a potential mediator for some of the NMDAR-related alterations observed in
schizophrenia. Consistently, substantial reductions of
D-aspartate and
NMDA were recently observed in the postmortem prefrontal cortex of schizophrenic patients. Here we show that DDO
mRNA expression is increased in prefrontal samples of schizophrenic patients, thus suggesting a plausible molecular event responsible for the
D-aspartate imbalance previously described. To investigate whether altered
D-aspartate levels can modulate
schizophrenia-relevant circuits and behaviors, we also measured the psychotomimetic effects produced by the NMDAR antagonist,
phencyclidine, in Ddo knockout mice (Ddo(-)(/-)), an animal model characterized by tonically increased
D-aspartate levels since perinatal life. We show that Ddo(-/-) mice display a significant reduction in
motor hyperactivity and prepulse inhibition deficit induced by
phencyclidine, compared with controls. Furthermore, we reveal that increased levels of
D-aspartate in Ddo(-/-) animals can significantly inhibit functional circuits activated by
phencyclidine, and affect the development of cortico-hippocampal connectivity networks potentially involved in
schizophrenia. Collectively, the present results suggest that altered
D-aspartate levels can influence neurodevelopmental brain processes relevant to
schizophrenia.