Experimental evidence is beginning to converge on an important role for dysregulation of
glutamate carboxypeptidase II (GCPII) in
schizophrenia. The goal of this study was to determine GCPII levels in postmortem brain specimens of patients with
schizophrenia,
bipolar disorder or
unipolar depression and age-matched control subjects. We used N-[N-(S)-1,3-dicarboxypropyl]carbamoyl]-S-3-[(125)I]iodo-
l-tyrosine ([(125)I]DCIT), a high-affinity radioligand for GCPII, to probe for GCPII expression in prefrontal cortex (PFC) and mesial temporal lobe, two brain regions implicated in the pathophysiology of
schizophrenia. We found that GCPII levels measured by [(125)I]DCIT quantitative autoradiography were significantly lower in the PFC and entorhinal cortex in patients with
schizophrenia compared to age-matched controls. Patients with
bipolar disorder also expressed significantly lower GCPII levels in PFC than controls. The decrease in [(125)I]DCIT binding in
schizophrenia and
bipolar disorder remained significant after adjusting for
drug abuse. A significant difference in GCPII levels was also observed between
schizophrenia relative to
bipolar disorder and depressed subjects in the hippocampus-stratum lucidum and between
schizophrenia and bipolar in the CA2 region of the hippocampus, with bipolar and depressed subjects expressing higher levels of GCPII than subjects with
schizophrenia. These differences in hippocampal GCPII levels may implicate differences in the etiologies of these
mental disorders. In summary, this study demonstrates a regional dysregulation of GCPII expression in the brain of patients with
schizophrenia and other
psychiatric disorders and supports a hypoglutamatergic state of the former illness. GCPII may represent a viable therapeutic target for intervention in
psychiatric disease.