Behavioral Neurobiology of Schizophrenia and Its Treatment

Akbarian S, Schahram Akbarian, Akbarian, Schahram

Epigenetic regulators of gene expression including DNA cytosine methylation and posttranslational histone modifications could play a role for some of the molecular alterations associated with schizophrenia. For example, in prefrontal cortex of subjects with schizophrenia, abnormal DNA or histone methylation at sites of specific genes and promoters is associated with changes in RNA expression. These findings are of interest from a neurodevelopmental perspective because there is increasing evidence that epigenetic markings for a substantial portion of genes and loci are highly regulated during the first years of life. Furthermore, there is circumstantial evidence that a subset of antipsychotic drugs, including the atypical, Clozapine, interfere with chromatin remodeling mechanisms. Challenges for the field include (1) no clear consensus yet regarding disease-associated changes, (2) the lack of cell-specific chromatin assays which makes it difficult to ascribe epigenetic alterations to specific cell populations, and (3) lack of knowledge about the stability or turnover of epigenetic markings at specific loci in (brain) chromatin. Despite these shortcomings, the study of DNA and histone modifications in chromatin extracted from diseased and control brain tissue is likely to provide valuable insight into the genomic risk architecture of schizophrenia, particularly in the large majority of cases for which a straightforward genetic cause still remains elusive,