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 1,
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.This work was
supported by Grant MH069675 from the National Institute of Health. The
authors thank Scott Sponheim and Irving Gottesman for their perspectives
and insights on various aspects of the manuscript.