01 September 2005
Med Sci Monit 2005; 11(9): HY39-45 :: ID: 428439
The "glutamate hypothesis" of schizophrenia has emerged from the findingthat phencyclidine (PCP) induces psychotic-like behaviors in rodents, possibly by blocking the N-methyl-D-aspartate(NMDA) subtype of glutamate receptor, thereby causing increased glutamate release. N-acetyl aspartylglutamate(NAAG), an endogenous peptide abundant in mammalian nervous systems, is localized in certain brain cells,including cortical and hippocampal pyramidal neurons. NAAG is synthesized from N-acetylaspartate (NAA)and glutamate, and NAA availability may limit the rate of NAAG synthesis. Although NAAG is known to havesome neurotransmitter-like functions, NAA does not. NAAG is a highly selective agonist of the type 3metabotropic glutamate receptor (mGluR3, a presynaptic autoreceptor) and can inhibit glutamate release.In addition, at low levels, NAAG is an NMDA receptor antagonist, and blocking of NMDA receptors may increaseglutamate release. Taken together, low central NAAG levels may antagonize the effect of glutamate atNMDA receptors and decrease its agonistic effect on presynaptic mGluR3; both activities could increaseglutamate release, similar to the increase demonstrated in the PCP model of schizophrenia. In this report,it is suggested that the central NAAG deficit, possibly through decreased synthesis or increased degradationof NAAG, may play a role in the pathogenesis of schizophrenia. Evidence is presented and discussed frommagnetic resonance, postmortem, animal model, schizophrenia treatment, and genetic studies. The centralNAAG deficit model of schizophrenia could explain the disease process, from the perspectives of bothneurodevelopment and neurodegeneration, and may point to potential treatments for schizophrenia.
Keywords: Dipeptides - metabolism, Brain - metabolism, Aspartic Acid - metabolism, Glutamic Acid - metabolism, Models, Neurological, Receptors, N-Methyl-D-Aspartate - metabolism, Schizophrenia - metabolism
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