Hypothesis: Minimal changes in neural transmission in schizophrenia: Decreased glutamatergic and GABAergic functions in the prefrontal cortex

As the pathophysiology, decreased glutamatergic neurotransmission in the postmortem prefrontal cortex of schizophrenics has been suggested to underlie the condition. But consistent reproducible results have not been seen with the molecular biological studies focused on examining glutamatergic parameters in schizophrenic brains. We noticed the lack of reproducibility of these studies and hypothesized that this was caused by “minimal (functional) changes” of schizophrenic pathophysiology that cannot be detected as a robust result by investigating only one marker (i.e., receptor). The authors then investigated glutamate levels, as well as mRNA expression of glutamate receptors and transporters simultaneously for the same schizophrenic and control brain samples, in order to detect the “minimal changes” of glutamatergic neurotransmission in schizophrenic synaptic clefts. The results showed a tendency of increased mGluRs and decreased EAAT2 mRNA in all Brodmann areas examined, but no significant difference was observed between schizophrenics and controls. To make these small changes of glutamatergic neurotransmission on the synaptic clefts more apparent, the “receptors/transporters ratio” (mGluRs/EAAT2 ratio) was calculated for each case and the results showed that the mGluRs/EAAT2 ratio was significantly increased in schizophrenics compared to controls. Glutamate levels, measured by HPLC, showed a decrease in the schizophrenics, but failed to reach statistical significance. The same phenomenon was recognized in our GABAergic study of schizophrenic brain. To interpret these results as a monism, the increase in mGluRs and the decrease of EAAT2 mRNA compensate for the decrease in glutamate transmission in the schizophrenic synaptic clefts. But these changes are small and failed to be statistically significant. The “receptors/transporters ratio” for each case magnified these changes, such that they became statistically significant.