Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder

Arch Gen Psychiatry. 2004 Jul;61(7):649-57. doi: 10.1001/archpsyc.61.7.649.


Background: Disturbances of gamma-aminobutyric acid interneurons in the cerebral cortex contribute to the pathophysiology of schizophrenia and bipolar disorder. The activity of these neurons is, in turn, modulated by glutamatergic inputs furnished by pyramidal neurons.

Objective: To test the hypothesis that glutamatergic inputs onto gamma-aminobutyric acid interneurons via the N-methyl-d-aspartate (NMDA) receptor are altered in the anterior cingulate cortex in schizophrenia and bipolar disorder.

Design: A double in situ hybridization technique was used to simultaneously label the messenger RNA (mRNA) for the NMDA NR(2A) subunit with (35)sulfur and the mRNA for the 67-kDa isoform of the gamma-aminobutyric acid synthesizing enzyme glutamic acid decarboxylase (GAD(67)) with digoxigenin.

Setting: Postmortem human brain studies.

Participants: We studied 17 subjects with schizophrenia, 17 subjects with bipolar disorder, and 17 normal control subjects.

Results: The density of all GAD(67) mRNA-containing neurons was decreased by 53% and 28%, in layers 2 and 5, respectively, in subjects with schizophrenia, whereas in subjects with bipolar disorder there was a 35% reduction in layer 2 only. For GAD(67) mRNA-containing neurons that co-expressed NR(2A)mRNA, their numerical density was decreased by 73% and 52%, in layers 2 and 5, respectively, in subjects with schizophrenia and by 60% in layer 2 in those with bipolar disorder. In the schizophrenia group, the density of the GAD(67)mRNA-containing neurons that did not co-express NR(2A)mRNA was also decreased by 42% in layer 2. In both disease groups, the expression level of NR(2A)mRNA in GAD(67) mRNA-containing cells was unaltered.

Conclusions: The density of gamma-aminobutyric acid interneurons that express the NMDA NR(2A)subunit appears to be decreased in schizophrenia and bipolar disorder. Future studies will address whether subpopulations of these neurons may be differentially affected in the 2 conditions.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Bipolar Disorder / enzymology
  • Bipolar Disorder / metabolism*
  • Cell Count
  • Digoxigenin / metabolism
  • Female
  • Gene Expression
  • Glutamate Decarboxylase / genetics
  • Glutamate Decarboxylase / metabolism*
  • Gyrus Cinguli / cytology
  • Gyrus Cinguli / enzymology
  • Gyrus Cinguli / metabolism*
  • Humans
  • In Situ Hybridization
  • Interneurons / cytology
  • Interneurons / enzymology
  • Interneurons / metabolism*
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Male
  • Middle Aged
  • Pyramidal Cells / cytology
  • Pyramidal Cells / enzymology
  • Pyramidal Cells / metabolism
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Schizophrenia / enzymology
  • Schizophrenia / metabolism*
  • gamma-Aminobutyric Acid / biosynthesis*


  • Isoenzymes
  • RNA, Messenger
  • Receptors, N-Methyl-D-Aspartate
  • gamma-Aminobutyric Acid
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1
  • Digoxigenin
  • N-methyl D-aspartate receptor subtype 2A