N-Phthalyl-l-Tryptophan (RG108), like Clozapine (CLO), Induces Chromatin Remodeling in Brains of Prenatally Stressed Mice

Schizophrenia (SZ), schizoaffective (SZA), and bipolar (BP) disorder are neurodevelopmental psychopathological conditions related, in part, to genetic load and, in part, to environmentally induced epigenetic dysregulation of chromatin structure and function in neocortical GABAergic, glutamatergic, and monoaminergic neurons. To test the above hypothesis, we targeted our scientific efforts on identifying whether the molecular epigenetic signature of postmortem brains of patients with SZ, SZA, and BP disorder are also present in the brains of adult mice born from dams prenatally restraint stressed (PRS) during gestation. The brains of PRS mice, which are similar to the brains of patients with SZ and BP disorder, show an ∼2-fold increased binding of DNMT1 to psychiatric candidate promoters (glutamic acid decarboxylase 67, Reelin, and brain-derived neurotrophic factor), leading to their hypermethylation, reduced expression, as well as the behavioral endophenotypes reminiscent of those observed in the above psychiatric disorders. To establish whether clozapine (CLO) produces its behavioral and molecular action through a causal involvement of DNA methylation/demethylation processes, we compared the epigenetic action of CLO with that of the DNMT1 competitive inhibitor N-phthalyl-l-tryptophan (RG108). The intracerebroventricular injection of RG108 (20 nmol/day per 5 days), similar to the systemic administration of CLO, corrects the altered behavioral and molecular endophenotypes that are typical of PRS mice. These results are consistent with an epigenetic etiology underlying the behavioral endophenotypic profile in PRS mice. Further, it suggests that PRS mice may be useful in the preclinical screening of antipsychotic drugs acting to correct altered epigenetic mechanisms.