N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia?
Schizophrenia is a severe mental disorder associated with a characteristic constellation of symptoms and neurocognitive deficits. At present, etiological mechanisms remain relatively unknown, although multiple points of convergence have been identified over recent years. One of the primary convergence points is dysfunction of N-methyl-d-aspartate (NMDAR)-type glutamate receptors. Antagonists of NMDAR produce a clinical syndrome that closely resembles, and uniquely incorporates negative and cognitive symptoms of schizophrenia, along with the specific pattern of neurocognitive dysfunction seen in schizophrenia. Genetic polymorphisms involving NMDAR subunits, particularly the GRIN2B subunit have been described. In addition, polymorphisms have been described in modulatory systems involving the NMDAR, including the enzymes serine racemase and d-amino acid oxidase/G72 that regulate brain d-serine synthesis. Reductions in plasma and brain glycine, d-serine and glutathione levels have been described as well, providing potential mechanisms underlying NMDAR dysfunction. Unique characteristics of the NMDAR are described that may explain the characteristic pattern of symptoms and neurocognitive deficits observed in schizophrenia. Finally, the NMDAR complex represents a convergence point for potential new treatment approaches in schizophrenia aimed at correcting underlying abnormalities in synthesis and regulation of allosteric modulators, as well as more general potentiation of pre- and post-synaptic glutamatergic and NMDAR function.
Kantrowitz
Joshua T
JT
Schizophrenia Research Center, Nathan Kline Institute for Psychiatric Research/New York University School of Medicine, 140 Old Orangeburg Road, Orangeburg, NY 10962, United States.
Javitt
Daniel C
DC
D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D006801:Humans; D007859:Learning Disabilities / Q000209:etiology; D008569:Memory Disorders / Q000209:etiology; D008954:Models, Biological; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D012559:Schizophrenia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D012678:Sensation Disorders / Q000209:etiology
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate