Translational and developmental perspective on N-methyl-D-aspartate synaptic deficits in schizophrenia.
Schizophrenia has long been approached from a translational perspective; however, new findings from the past decade have radically affected the dominant accounts of this illness. It is now possible to derive a consistent account of one contributing cause of schizophrenia across multiple levels of analysis, from genes to receptors, functional neuroanatomy, cognition, and symptoms. To this end, we summarize the data attributing the disorganization symptoms of schizophrenia to a failure of executive, prefrontal cortical processes. We describe the hypothesis that this failure reflects an impairment in N-methyl-D-aspartate (NMDA) glutamatergic neurotransmission, that is likely to involve both the dysregulated function of NMDA synapses, as well as the physical loss of NMDA synapses, particularly in prefrontal cortex. Dysregulation in NMDA synaptic function can be in turn attributed to polymorphisms in a variety of genes (regulator of G-protein signaling 4, dystrobrevin binding protein I, neuregulin-1, D-amino acid oxidase activator, and others) that have been linked to schizophrenia and are likely to impact NMDA-mediated synaptic neuroplasticity. Although the science of schizophrenia is not yet at a point where any domain or set of findings provides strong constraints across other levels of analysis, the further development of evidence for this chain of causation can provide increasingly strong tests of the NMDA synapse deficit theory.
MacDonald
Angus W
AW
Department of Psychology, University of Minnesota, Minneapolis 55455, USA. angus@umn.edu
Chafee
Matthew V
MV
D002352:Carrier Proteins / Q000235:genetics; D003072:Cognition Disorders / Q000453:epidemiology / Q000503:physiopathology; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D006801:Humans; D033183:Interdisciplinary Communication; D047908:Intracellular Signaling Peptides and Proteins; D016202:N-Methylaspartate / Q000172:deficiency / Q000378:metabolism*; D009415:Nerve Net / Q000378:metabolism / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics; D020890:Neuregulin-1; D009473:Neuronal Plasticity / Q000502:physiology; D017397:Prefrontal Cortex / Q000503:physiopathology; D017729:Presynaptic Terminals / Q000378:metabolism*; D011582:Psychological Theory; D020710:RGS Proteins / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics; D012559:Schizophrenia / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D012919:Social Behavior
D002352:Carrier Proteins; C475071:DAOA protein, human; C432416:DTNBP1 protein, human; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D047908:Intracellular Signaling Peptides and Proteins; C094131:NRG1 protein, human; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D020710:RGS Proteins; D018094:Receptors, Metabotropic Glutamate; C098799:RGS4 protein; D016202:N-Methylaspartate