Abstract
BackgroundWe have previously reported that the expression of the messenger ribonucleic acid (mRNA) for the NR2A subunit of the N-methyl-D-aspartate (NMDA) class of glutamate receptor was decreased in a subset of inhibitory interneurons in the cerebral cortex in schizophrenia. In this study, we sought to determine whether a deficit in the expression of NR2A mRNA was present in the subset of interneurons that contain the calcium buffer parvalbumin (PV) and whether this deficit was associated with a reduction in glutamatergic inputs in the prefrontal cortex (PFC) in schizophrenia.MethodsWe examined the expression of NR2A mRNA, labeled with a 35S-tagged riboprobe, in neurons that expressed PV mRNA, visualized with a digoxigenin-labeled riboprobe via an immunoperoxidase reaction, in twenty schizophrenia and twenty matched normal control subjects. We also immunohistochemically labeled the glutamatergic axon terminals with an antibody against vGluT1.ResultsThe density of the PV neurons that expressed NR2A mRNA was significantly decreased by 48-50% in layers 3 and 4 in the subjects with schizophrenia, but the cellular expression of NR2A mRNA in the PV neurons that exhibited a detectable level of this transcript was unchanged. In addition, the density of vGluT1-immunoreactive boutons was significantly decreased by 79% in layer 3, but was unchanged in layer 5 of the PFC in schizophrenia.ConclusionThese findings suggest that glutamatergic neurotransmission via NR2A-containing NMDA receptors on PV neurons in the PFC may be deficient in schizophrenia. This may disinhibit the postsynaptic excitatory circuits, contributing to neuronal injury, aberrant information flow and PFC functional deficits in schizophrenia.
Highlights
We have previously reported that the expression of the messenger ribonucleic acid for the NR2A subunit of the N-methyl-D-aspartate (NMDA) class of glutamate receptor was decreased in a subset of inhibitory interneurons in the cerebral cortex in schizophrenia
Density of PV messenger ribonucleic acid (mRNA)+ Neurons Consistent with previous observations [26,37], we found that the number of cells that expressed a detectable level of PV mRNA was not altered in subjects with schizophrenia (F = 3.35; df = 1, 38; P = 0.07)
Convergent lines of evidence suggest that glutamatergic neurotransmission on PV-containing neurons via NMDA receptors appears to be deficient in schizophrenia
Summary
We have previously reported that the expression of the messenger ribonucleic acid (mRNA) for the NR2A subunit of the N-methyl-D-aspartate (NMDA) class of glutamate receptor was decreased in a subset of inhibitory interneurons in the cerebral cortex in schizophrenia. The prefrontal cortex (PFC) plays an important role in the temporal organization of behavior [1,2] by temporarily maintaining "on-line" internal representations of perceptual, cognitive and emotive information in order to guide sequential, contextually meaningful behavior [3]. This (page number not for citation purposes). The integrity of PFC functions depends on the delicate interplay of feedback and feedforward mechanisms of modulation of cortical inhibitory activities via activation of glutamate receptors on GABA interneurons [8,9,13,14]
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