Neurobiology of glutamatergic abnormalities in schizophrenia

A variety of studies have implicated abnormalities of the glutamatergic systems in schizophrenia. Some of this evidence is based on the similarities of some of the symptoms of schizophrenia and the behavioral effects of dissociative anesthetics such as ketamine. More direct evidence has come from biological studies defining abnormalities at multiple levels of the glutamate neurotransmission cascade. These have included abnormalities in the receptor binding properties of the various classes of ionotropic glutamate receptors (AMPA, kainate, NMDA); mRNA expression levels of different subunits of each of the members of the ionotropic class of glutamate receptors; mRNA expression of glutamate receptor-specific binding and membrane anchoring proteins such as PSD-95; and alterations in the activity of the principal enzyme responsible for the synthesis of the glutamate from glutamine, phosphate activated glutaminase. Preliminary evidence from proton magnetic resonance spectroscopy studies also supports a role for increased levels of glutamate, or glutamine and glutamate, in schizophrenia. The evidence reviewed in this article, when viewed as a whole, suggests that the disruption or disregulation of glutamatergic systems contribute significantly to the pathophysiology and potentially to some of the symptoms of schizophrenia and defines a necessary role for continued investigation of this pivotal neurotransmitter system in schizophrenia.