Differential binding of CREB and REST/NRSF to NMDAR1 promoter is associated with the sex-selective cognitive deficit following postnatal PBDE-209 exposure in mice

Abstract

Neonatal exposure to decabromodiphenyl ether (PBDE-209), a ubiquitous environmental pollutant, affects cognitive performances in the later stage of life in a sex-dependent manner. PBDE-209 interferes with glutamatergic signaling and N-methyl-D-aspartate receptor (NMDAR) subunits with unresolved regulatory mechanisms. This study exposed male and female mice pups through postnatal day (PND) 3-10 to PBDE-209 (oral dose: 0, 6, or 20 mg/kg body weight). The frontal cortex and hippocampus, collected from neonate (PND 11) and young (PND 60) mice, were analyzed for cAMP response elementbinding protein (CREB) and RE1-silencing transcription factor/ Neuron-restrictive silencer factor (REST/NRSF) binding to NMDAR1 promoter and expression of NMDAR1 gene by electrophoretic mobility shift assay and semi-quantitative RT-PCR respectively. Behavioral changes were assessed using spontaneous alternation behavior and novel object recognition tests in young mice. In neonates, the binding of CREB was increased, while REST/NRSF was decreased signi cantly to their cognate NMDAR1 promoter sequences at the high dose of PBDE-209 in both the sexes. This reciprocal pattern of CREB and REST/NRSF interactions correlates with the up-regulation of NMDAR1 expression. Young males followed a similar pattern of CREB and REST/NRSF binding and NMDAR1 expression as in neonates. Surprisingly, young females did not show any alteration when compared to age-matched controls. Also, we found that only young males showed working and recognition memory de cits. These results indicate that early exposure to PBDE-209 interferes with CREB-and REST/NRSF-dependent regulation of the NMDAR1 gene in an acute setting. However, long-term effects persist only in young males that could be associated with cognitive impairment.

REST Is Not Resting: REST/NRSF in Health and Disease

“…CDRI-08, the ethanolic extract of a nootropic plant Bacopa monnieri, could attenuate the impairment and restore the binding of REST to NR1 promotor [142]. Interestingly, the early acute exposure to PBDE-209 interferes with the regulation of NMDAR1 by (cAMP-response element-binding protein) CREB and REST, however, long-term effects persist only in young males that could be associated with cognitive impairment [143]. Further, the reasoning skill were not affected by the VNTR and rs2228991 variants of REST in a young Chinese Han population [144].…”