Localization of NAAG-related gene expression deficits to the anterior hippocampus in schizophrenia.
N-acetyl aspartyl glutamate (NAAG) is an endogenous agonist at the metabotropic glutamate receptor 3 (mGluR3,GRM3) receptor and antagonist at the N-methyl d-aspartate (NMDA) receptor, both receptors important to the pathophysiology of schizophrenia. Glutamate carboxypeptidase II (GCPII), an enzyme that metabolizes NAAG, is also implicated in this illness. In this study, we conducted in situ hybridization experiments to examine expression of mGluR3 and GCPII transcripts along the rostrocaudal axis of the human postmortem hippocampus. We hypothesized that we would find changes in mGluR3 and/or GCPII in the AH but not posterior hippocampus (PH) in schizophrenia. We compared mRNA levels of these genes in the dentate gyrus (DG) and cornu ammonis (CA)1 and CA3 of AH and PH in 20 matched pairs of control and schizophrenia cases. In controls, mGluR3 is highly expressed in the DG and at lower levels in CA1 and CA3 while GCP II is expressed at similar levels in these regions. Group comparisons show a significant reduction of GCPII mRNA level in the AH in schizophrenia. Post hoc analyses reveal this difference is localized to the CA1 region. In addition, we find a significant positive correlation between GCPII and mGluR3 mRNA in the CA3 of the control AH (r=0.66, p=0.008) which is not present in schizophrenia (r=0.096, p=0.76). This may reflect a disrupted functional interaction between NAAG and mGluR3 in CA3 in schizophrenia. These data suggest that NAAG-mediated signaling is disrupted in the AH in schizophrenia and localize the defect to the CA1 and CA3 regions.
Ghose
Subroto
S
University of Texas Southwestern Medical Center, Dallas, TX 75390-9127, USA. subroto.ghose@utsouthwestern.edu
Chin
Ronald
R
Gallegos
Analysa
A
Roberts
Rosalinda
R
Coyle
Joseph
J
Tamminga
Carol
C
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000954:Antigens, Surface / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D015536:Down-Regulation / Q000235:genetics*; D005260:Female; D043425:Glutamate Carboxypeptidase II / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D012333:RNA, Messenger / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics* / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics / Q000473:pathology*; D055815:Young Adult
D000954:Antigens, Surface; D012333:RNA, Messenger; D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II