The exact mechanisms underlying schizophrenia remain unknown, though theories abound. Recent studies suggest that particular cell types and biological processes in the schizophrenic cortex have a pseudo-immature status in which the molecular properties partially resemble those in the normal immature brain. However, genome-wide gene expression patterns in the brains of patients with schizophrenia and those of normal infants have not been directly compared. Here, we show that the gene expression patterns in the schizophrenic prefrontal cortex (PFC) resemble those in the juvenile PFC.
We conducted a comparative analysis using microarray data sets derived from the dorsolateral PFC (DLFC) of patients with schizophrenia and the DLFC of developing normal human brains, revealing a striking similarity. The results were replicated in a second DLFC data set and a medial PFC (MFC) data set.
We also show that more than half of genes representing transcriptional immaturity of schizophrenic PFC were developmentally regulated in fast-spiking interneurons, astrocytes, and oligodendrocytes. These results may imply the pseudo-immaturity of these cell types in schizophrenic PFC.
To test whether medications, which often confound the results of postmortem analyses, effect on the juvenile-like gene expressions in schizophrenic PFC, we compared the gene expression patterns showing transcriptomic immaturity of the schizophrenia PFC with those of rodent PFC treated with antipsychotic drugs. The results showed no apparent similarities between the two conditions, suggesting that the juvenile-like gene expression patterns observed in the schizophrenic PFC could not be accounted for by medication effects. The developing human PFC showed a gene expression pattern similar to that of the PFC of naive Schnurri-2 knockout mice, an animal model of schizophrenia with good face and construct validity. This result also supports the idea that the transcriptional immaturity in of the schizophrenic PFC is not due to medication effects.
Collectively, our results provide evidence that pseudo-immaturity of PFC resembling that of the juvenile brain may be an endophenotype for schizophrenia.