With support from a NARSAD Grant in 1996, Eric J. Nestler, M.D., Ph.D., and colleagues identified a novel transcription factor that determines the long-lasting consequences of stress and of several classes of antipsychotic medications on the brain. Transcription factors are proteins that control which genes are turned on or off in the genome. The team found that first and second generation antipsychotic medications induce the transcription factor, DeltaFosB, in several brain regions including regions of the prefrontal cortex. DeltaFosB is unique among transcription factors in that it is very long-lived: once induced it persists in brains for relatively long periods of time. It is thus an ideal molecular mechanism underlying stable brain adaptations. The finding opened a new pathway for treatment development efforts for a wide range of psychiatric disorders.
More recently, Dr. Nestler and colleagues found that DeltaFosB is expressed at higher levels in these same brain regions in people with schizophrenia, but only those actively treated with antipsychotic medications. Medication-free patients display normal DeltaFosB levels. They also have demonstrated recently, using viral-mediated gene transfer in animal models, that the induction of DeltaFosB in the prefrontal cortex region of rodents exerts negative effects on several behavioral domains. These data support the view that DeltaFosB induction in the prefrontal cortex in response to antipsychotic medication administration mediates some of the deleterious effects of these medications, and that perhaps antagonists of DeltaFosB now under development might be useful as an adjunct to optimize the utility of antipsychotic treatment.