Subchronic Administration of Phencyclidine Produces Hypermethylation in the Parvalbumin Gene Promoter in Rat Brain

Abstract

Subchronic PCP administration results in a specific hypermethylation in the Pvalb promoter which may contribute to parvalbumin deficits in this animal model of psychosis.

Increased DNA Methylation in the Parvalbumin Gene Promoter is Associated with Methamphetamine Dependence

“…While it is conceivable that individuals with higher levels of PVALB promoter methylation may be susceptible to METH-dependent psychosis, studies in animals suggest PVALB hypermethylation seems more likely to be a consequence rather than a cause of METH dependence. The observations that hypermethylation in equivalent sequences in the PV gene promoter of mice born to mothers following Mn-induced neurotoxicity [15], and of rats previously undergoing a subchronic regime of phencyclidine administration [16], both indicate that neuro-and psychoactive substances can have specific effects on PV gene methylation. In particular, the latter study and our findings both support an association between PV gene hypermethylation and psychosis, since phencyclidine administration is used as a model for some of the symptoms of schizophrenia.…”

“…A previous study has shown an increase in DNA methylation in the pvalb gene promoter in mouse hippocampus after manganeseinduced neuronal damage [15]. We have hypothesized that effects on DNA methylation of the PVALB promoter region might reduce PV expression and relate to the PV deficits in schizophrenia and models of psychosis, and recently reported that hypermethylation at one site of the equivalent Pvalb gene promoter sequence was observed in rat prefrontal cortex and hippocampus after phencyclidine administration [16].…”

“…The present study aimed to investigate whether there was a change in methylation in the promoter sequence of the PVALB gene in DNA isolated from blood samples taken from subjects with METH dependence or METH-dependent psychosis. Figure 1), overlapping the equivalent sequence previously studied in rat [16], AAA AAA TCA AAA AAT TCC CTT TCC -3' (reverse) (Eurofins MWG Operon, Ebersberg, Germany) using PyroMark PCR kit (Qiagen, UK) according to the manufacturer's protocol.…”

Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia

“…16 Based on the fact that a peripubertal antioxidant treatment can abolish oxidative stress and rescue PVI/PNN deficit in the NVHL rat model, 41 we propose a hypothesis in which redox dysregulation/oxidative stress halts normal PVI maturation in the prefrontal cortex without causing their death, 82 possibly via epigenetic mechanisms. 102, 103 The deleterious effect of oxidative stress on PNN integrity 16 may be also central to the failure of PV circuits to properly mature as PNN is crucial for PVI maturation and synapse formation. As consequence, oxidative stress might impair the PVI-associated network plasticity, that is, activity-dependent regulation of the number of excitatory and inhibitory synapses on PVIs.…”

“…Furthermore, phencyclidine administration results in hypermethylation of CpG sites in the promoter of PV gene which includes binding sites for Nrf2, the master regulator of antioxidant defense. 102 This may also contribute to oxidative damage and PV deficits. Concerning the environmental 'two-hit' model, we propose that a sub-threshold immune challenge primes microglia to be activated at pre-pubertal stress 49 resulting in ROS production and PVI/PNN deficits.…”