Another enzyme, Mll1, may play a role in the epigenetic actions. For genes to be turned on, temporary structural changes in certain proteins - histones - must take place to expose the genes' blueprints in DNA. The researchers found evidence that, in schizophrenia, changes in Mll1 activity may interfere with this process in histones whose alterations enable the GAD1 blueprint to be exposed.
The researchers also showed, in mice, that antipsychotic medications like clozapine appear to correct this epigenetic flaw. This raises the possibility of developing new medications aimed at correcting defects in the mechanisms involved.
Finding more precise molecular targets for development of new schizophrenia medications is a key effort, because it can lead to more effective treatments with fewer side effects. Clozapine and other current antipsychotic medications are effective for many patients, but not all, and they can cause side effects severe enough that some people choose to stop treatment.
The researchers also found that people with three different variations of the GAD1 gene variations previously associated with schizophrenia also were more likely to have indicators of a malfunction in brain development. Among them were indicators of altered epigenetic actions related to GABA synthesis.
Weve known that schizophrenia is a developmental disease, and that something happens in the maturation of the prefrontal cortex during this vulnerable period of life. Now were beginning to find out what it is, and that sets the stage for better ways of preventing and treating it, Akbarian said.
|Contact: Susan Cahill|
NIH/National Institute of Mental Health