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Guochuan Tsai, MD, PhD; Lucius A. Passani, MS; Barbara S. Slusher, PhD; Ruth Carter; Lee Baer, PhD; Joel E. Kleinman, MD, PhD; Joseph T. Coyle, MD

Arch Gen Psychiatry. 1995;52(10):829-836.

Abstract
Background
Schizophrenia has been hypothesized to be caused by a hypofunction of glutamatergic neurons. Findings of reduced concentrations of glutamate in the cerebrospinal fluid of patients with schizophrenia and the ability of glutamate-receptor antagonists to cause psychotic symptoms lend support to this hypothesis. N-acetylaspartylglutamate (NAAG), a neuropeptide that is highly concentrated in glutamatergic neurons, antagonizes the effects of glutamate at N-methyl-D-aspartate receptors. Moreover, NAAG is cleaved to glutamate and N-acetylaspartate by a specific peptidase, N-acetyl-—linked acidic dipeptidase (NAALADase). To test the glutamatergic hypothesis of schizophrenia, we studied the NAAG-related glutamatergic variables in postmortem brains from patients with schizophrenia, neuroleptic-treated controls, and normal individuals, with particular emphasis on the prefrontal cortex and hippocampus.

Method
Different regions of frozen brain tissue from three different groups (patients with schizophrenia, neuroleptictreated controls, and normal controls) were assayed to determine levels of NAAG, N-acetylaspartate, NAALADase, and several amino acids, including aspartate and glutamate.

Results
Our study demonstrates alterations in brain levels of aspartate, glutamate, and NAAG and in NAALADase activity. Levels of NAAG were increased and NAALADase activity and glutamate levels were decreased in the schizophrenic brains. Notably, the changes in NAAG level and NAALADase activity in schizophrenic brains were more selective than those for aspartate and glutamate. In neuroleptic-treated control brains, levels of aspartate, glutamate, and glycine were found to be increased.

Conclusions
The changes in levels of aspartate, glutamate, NAAG, and NAALADase are prominent in the prefrontal and hippocampal regions, where previous neuropathological studies of schizophrenic brains demonstrate consistent changes. These findings support the hypothesis that schizophrenia results from a hypofunction of certain glutamatergic neuronal systems. They also suggest that the therapeutic efficacy of neuroleptics may be related to increased glutamatergic activity.

Author Affiliations
From the Laboratory of Molecular and Developmental Neuroscience and the Department of Psychiatry, Harvard Medical School, and Massachusetts General Hospital, Boston (Drs Tsai, Slusher, Baer, and Coyle, and Mr Passani and Ms Carter); and the Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health Neuroscience Center at St Elizabeths Hospital, Washington, DC (Dr Kelinman). Dr Slusher is currently affiliated with Guilford Pharmaceuticals, Baltimore, Md.

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