The glutamatergic dysfunction hypothesis for schizophrenia

Abstract

Schizophrenia is a syndrome, undoubtedly with multiple etiologies, that variably exhibits several features including positive and negative symptoms, cognitive deficits, onset in young adulthood, and deterioration from the previous level of function. This review will examine the growing evidence that dysfunction of corticolimbic glutamatergic neurotransmission may contribute to or account for the manifestations of schizophrenia. Glutamatergic neurons represent the primary excitatory afferent and efferent systems innervating the cortex, limbic regions, and striatum. The postsynaptic actions of glutamate are mediated by a family of glutamate-gated ion channels that permit the influx of sodium and calcium, thereby depolarizing (exciting) neurons. One of these receptors, the N-methyl-D-aspartate (NMDA) receptor, is the site of action of psychotomimetics such as phencyclidine and related anesthetics, which can reproduce in normal individuals most of the symptomatic features of schizophrenia. An endogenous antagonist at the NMDA receptor, N-acetyl-aspartyl glutamate, appears to have enhanced activity in the frontal cortex and hippocampal formation in persons with this disorder. Glutamatergic dysfunction may be particularly relevant to those forms of schizophrenia in which negative symptoms, cognitive deficits, and deterioration are prominent features. In support of this inference, clinical studies have shown that drugs that enhance NMDA-receptor function reduce negative symptoms and cognitive deficits in persons with chronic schizophrenia who are receiving neuroleptics. Thus, dysfunction of glutamatergic neurotransmission represents an important organizational focus for research on the complex manifestations of schizophrenia.