It appears that a heterogeneous population of interneurons is implicated in schizophrenia. Further studies are needed to determine whether specific interneuron subpopulations are altered or whether common or distinct upstream pathways are responsible for interneuron deficits in schizophrenia.

Blockade of N-methyl-D-aspartate receptors (NMDARs) produces behavior in healthy people that is similar to the psychotic symptoms and cognitive deficits of schizophrenia and can exacerbate symptoms in people with schizophrenia. However, an endogenous brain disruption of NMDARs has not been clearly established in schizophrenia. We measured mRNA transcripts for five NMDAR subunit mRNAs and protein for the NR1 subunit in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia and control (n=74) brains. Five NMDAR single-nucleotide polymorphisms (SNPs) previously associated with schizophrenia were tested for association with NMDAR mRNAs in postmortem brain and for association with cognitive ability in an antemortem cohort of 101 healthy controls and 48 people with schizophrenia. The NR1 subunit (mRNA and protein) and NR2C mRNA were decreased in postmortem brain from people with schizophrenia (P=0.004, P=0.01 and P=0.01, respectively). In the antemortem cohort, the minor allele of NR2B rs1805502 (T5988C) was associated with significantly lower reasoning ability in schizophrenia. In the postmortem brain, the NR2B rs1805502 (T5988C) C allele was associated with reduced expression of NR1 mRNA and protein in schizophrenia. Reduction in NR1 and NR2C in the DLPFC of people with schizophrenia may lead to altered NMDAR stoichiometry and provides compelling evidence for an endogenous NMDAR deficit in schizophrenia. Genetic variation in the NR2B gene predicts reduced levels of the obligatory NR1 subunit, suggesting a novel mechanism by which the NR2B SNP may negatively influence other NMDAR subunit expression and reasoning ability in schizophrenia.

Schizophrenia and bipolar disorder share a number of common features, both symptomatically and biologically. Abnormalities in the neuroimmune and the stress-signaling pathways have been previously identified in brains of individuals with both diseases. However, the possible relationship between abnormalities in stress and neuroimmune signaling within the cortex of people with psychotic illness has not been defined. To test the hypothesis that combined alterations in brain stress responsiveness and neuroimmune/inflammatory status are characteristic of some individuals suffering from major mental illness, we examined gene expression in the Stanley Array Cohort of 35 controls, 35 individuals with schizophrenia and 34 individuals with bipolar disorder. We used levels of 8 inflammatory-related transcripts, of which SERPINA3 was significantly elevated in individuals with schizophrenia (F(2,88)=4.137, P<0.05), and 12 glucocorticoid receptor signaling (stress) pathway transcripts previously examined, to identify two clusters of individuals: a high inflammation/stress group (n=32) and a low (n=68) inflammation/stress group. The high inflammation/stress group has a significantly greater number of individuals with schizophrenia (n=15), and a trend toward having more bipolar disorder individuals (n=11), when compared with controls (n=6). Using these subgroups, we tested which microarray-assessed transcriptional changes may be associated with high inflammatory/stress groups using ingenuity analysis and found that an extended network of gene expression changes involving immune, growth factors, inhibitory signaling and cell death factors also distinguished these groups. Our work demonstrates that some of the heterogeneity in schizophrenia and bipolar disorder may be partially explained by inflammation/stress interactions, and that this biological subtype cuts across Diagnostic and Statistical Manual of Mental Disorders (DSM)-defined categories.