Increased glutamatergic activity was postulated to be present in neural circuits within the brains of schizophrenics.18
Increased excitatory activity emanating from glutamatergic neurons can promote oxidative stress and apoptosis in psychotic disorders.19
To test the hypothesis that oxidative stress might be present in schizophrenia and possibly also in bipolar disorder, a microarray-based gene expression profiling study was conducted in the hippocampus of normal controls, schizophrenics, and bipolars.20
As shown in , the results demonstrated a striking difference in the pattern of expression of 24 different genes associated with this signaling pathway in schizophrenics and bipolars. While the bipolar subjects showed an increased expression of proapoptotic genes, such as FAS ligand and its receptor, tumor necrosis factor alpha, perforin, several caspases, c-myc, and BAK, schizophrenics showed the opposite pattern, ie, many proapoptotic genes, such as granzyme B and BAX, were either downregulated or showed no change in regulation. Conversely, the antiapoptotic gene, Bcl-2, was found to be upregulated in schizophrenics but downregulated in bipolars. Additionally, bipolars showed a highly significant downregulation of several different antioxidation genes, including superoxide dismutase, glutathione peroxidase, glutathione synthase, and catalase, changes that can lead to the accumulation of reactive oxygen species and cellular toxicity.21
Overall, the results in bipolars were consistent with a previous study in which genes involved in the regulation of the electron transport chain were also found to be markedly downregulated.22
It is noteworthy that a study of DNA damage in the anterior cingulate cortex demonstrated a marked reduction in schizophrenics but no change in bipolars.23
Subsequently, a double localization of single-stranded DNA breaks in cells expressing GAD67 messenger RNA demonstrated a significant increase in bipolars.24
Of course, it is important to consider whether neuroleptic drugs may have played a role in these changes in the expression of genes involved in the regulation of oxidation reactions. A careful analysis of the regulation of both pro- and antiapoptotic genes in patients with schizophrenia and bipolar disorder who were receiving low versus high doses of these drugs during the year prior to death are not consistent with this possibility.
Fig. 1. Schematic diagrams depicting changes in the expression of genes associated with a mitochondrial oxidation, anti-oxidation regulation, and an L-type calcium channel in bipolar disorder (left) and schizophrenia (right). There are fundamental differences (more ...)
Taken together, the results described above support the idea that schizophrenia and bipolar disorder involve a common cellular phenotype, one in which dysfunctional GABAergic interneurons contribute to abnormal information processing in the limbic lobe. As suggested by others,1
the endophenotypes for such cells may nevertheless be quite different in the 2 different forms of psychotic disorder. It might be concluded then that the mechanisms responsible for the decreased amount of GABAergic activity may be fundamentally different in schizophrenia and bipolar disorder. In bipolars, the gene expression profiling findings clearly point to molecular changes, such as activation of the apoptosis cascade and the L
-type calcium channel 1D, but suppression of the antioxidant pathways, that could play a central role in the pathophysiology of this disorder. In schizophrenia, on the other hand, it is unlikely that GABA cell dysfunction involves oxidative mechanisms because similar changes were not observed. Indeed, the regulation of genes associated with apoptosis was suppressed to a large extent. It is important to emphasize, however, that reductions of interneuronal numbers have been found to be reduced in sector CA2 of subjects with both disorders bipolar disorder and schizophrenia. If the apoptotic cascade were not activated in schizophrenia, why would reduced numbers of GABA cells be found in these patients? One possible explanation for this paradox is that interneurons in the hippocampus of schizophrenics are, indeed, being subjected to oxidative stress but only during an earlier phase of the illness. If cells drop out in the schizophrenics, but the apoptotic cascade is subsequently downregulated, the overall numbers of GABA cell could remain stable. If this were the case, it would be difficult to explain the results of a study in which the numerical density of interneurons in CA2 of schizophrenics and bipolars were found to be the same.25
If apoptosis is indeed killing GABA cells in CA2 of bipolars, these cells would be expected to drop out of the neuronal population in that sector. If the regulation of apoptosis genes continues to be upregulated, as it appears to be in bipolar disorder, then one might expect to find that there is an ongoing process of cell loss in these patients as the illness continues. How then can the observation that the number of interneurons is the same in sector CA2 of the bipolars and the schizophrenics? One hypothesis that could account for this apparent discrepancy is that neurons in the bipolars that undergo apoptotic cell death are continually being replaced through active neurogenesis. In this setting, newly generated cells and cells that are dying would coexist in a relative steady state, such that the overall numbers in CA2 would not appear to be changing. An argument in favor of this hypothesis is that evidence for ongoing apoptosis comes from a study of DNA fragmentation in the anterior cingulate cortex. Specifically, increased DNA damage was observed in GABA cells of the anterior cingulate cortex of bipolar subjects but not schizophrenics.24
Analogous data for the hippocampus, particularly sector CA2, is not available and it is not necessarily the case that a similar pattern would be observed in this latter subregion.