Disease-specific alterations in glutamatergic neurotransmission on inhibitory interneurons in the prefrontal cortex in schizophrenia

Abstract

Glutamatergic modulation of inhibitory interneurons plays a crucial role in shaping the flow of information in the cerebral cortex. In a cohort of postmortem human brains from schizophrenia (n=20), bipolar disorder (n=20) and normal control (n=20) subjects, we colocalized the mRNA for the N-methyl-d-aspartate (NMDA) receptor NR2A subunit, labeled with [35S], and the mRNA for the gamma-aminobutyric acid (GABA) synthesizing enzyme glutamic acid decarboxylase (GAD)67, labeled with digoxigenin. We found that the density of GAD67+ neurons in layers 2-5 of the prefrontal cortex was decreased by 27-36% in both schizophrenia and bipolar disorder. In addition, the density of the GAD67+/NR2A+ neurons was decreased by 57% and 49% in layers 3 and 4, respectively, in schizophrenia, but it was unchanged in bipolar disorder. These findings raise the possibility that glutamatergic innervation of inhibitory interneurons via the NMDA receptor in the prefrontal cortex may be selectively altered in schizophrenia.

Figure 1

Photomicrograph of a double-labeled neuron with silver grains superimposed onto the digoxigenin reaction product. Scale bar=5 µm.

Figure 2

(A) Mean density of all neurons that express GAD₆₇ mRNA. (B) Mean density of GAD₆₇ mRNA-expressing neurons that also express NR2A mRNA. Asterisks indicate statistically significant difference at p=0.01. Error bars represent SEM.

Figure 3

Grain density distribution is not significantly different between the 3 diagnosis groups, suggesting that the amount of NR2A mRNA being expressed by GABA interneurons with experimentally detectable transcript level is not altered in schizophrenia or bipolar disorder.