Pregnane X Receptor Deletion Modifies Recognition Memory and Electroencephalographic Activity

Abstract

Nuclear receptors (NR) are emerging as key players in the central nervous system (CNS) with reported implications in physiological and pathophysiological conditions. While a number of NR has been studied, it is unknown whether invalidation of the pregnane xenobiotic receptor (PXR, NR1I2) corresponds to neurological modifications in the adult brain. PXR−/− C57BL/6 J and wild-type mice were used to investigate: (i) recognition memory, motor coordination, and anxiety-like behaviors; (ii) longitudinal video-electroencephalographic (EEG) recordings and frequency wave analysis; (iii) neurovascular structures by histological evaluation and expression of the cerebrovascular tight junctions ZO1 and CLDN5. Absence of PXR was associated with anxiety-like behavior and recognition memory impairment in adult mice. The latter was simultaneous to an EEG signature of lower theta frequency during sleep and abnormal delta waves. Neurophysiological changes did not correspond to significant structural changes in the adult brain, expect for a localized and minor increase in the fronto-parietal neurovascular density and reduced ZO1, but not CLDN5, expression in isolated brain capillaries. Our results converge with existing evidence supporting a link between NR expression and brain physiology. Although the exact modalities remain to be elucidated, the possibility that extra-physiological modulation of PXR may constitute a pathophysiological entry point or a molecular target for brain diseases is proposed.

Varying modalities of perinatal exposure to a pesticide cocktail elicit neurological adaptations in mice and zebrafish

“…sleep/immobility, and avoiding all motion artifacts. Periodogram Power Bands (Neuroscore) was calculated for all EEG and the relative abundance of each 0.5 Hz increment (0.5-80 Hz) was quantified (Boussadia et al, 2018(Boussadia et al, , 2016Ichkova et al, 2020). As we routinely perform and we previously described (Ichkova et al 2020, Zub et al 2019, spike or seizure analysis was executed as follow: 1) setting a threshold for spike detection of 2.5 x times the standard deviation of the baseline; 2) minimum and maximum spike duration (1 and 100 ms); 3) minimum train-spike duration 5s with a minimum number of spikes of n= 5 (at least 1Hz).…”

Garcinoic acid prevents β-amyloid (Aβ) deposition in the mouse brain

“…Important enough, GA shows much lower cytotoxicity compared with δ-T3, thus allowing treatments with much higher doses; furthermore, the more hydrophilic properties of GA may favor compound permeability through the blood-brain barrier. The fact that GA is available to the mouse brain and, along with PPARγ, it up-regulates PXR expression of this tissue, suggests other pharmacological applications, including anxiety-like behavior and recognition memory ( 39 ), and blood barrier function modulation ( 40 ) that are all PXR-dependent processes. Other therapeutic effects of GA could be anticipated in lipid and metabolic disorders associated with higher demand of ApoE activity or unfavorable APOE haplotypes ( 41 , 42 ).…”

The constitutive androstane receptor and pregnane X receptor in the brain

“…Recent studies have proposed that alterations in NR1I2 and NR1I3 function could impair the expression of tight junction proteins at the BBB since deletion of NR1I2 and NR1I3 in rats leads to reduced expression of zonula occuldens-1 protein in isolated brain microvessels, with no changes in claudin-5 expression reported (Boussadia et al, 2016;Boussadia et al, 2018). Although this is the only evidence available to date at brain level, it is supported by a previous study that demonstrated the relationship between NR1I2 and expression of TJ proteins in the intestine, in which NR1I2 (−/−) mice exhibited higher intestinal permeability (Venkatesh et al, 2014).…”

“…More recently, studies report that deletion of NR1I3 and NR1I2 in rodents severely impairs recognition memory and increases development of anxiety-like behaviours (Boussadia et al, 2016;Boussadia et al, 2018). Furthermore, both studies associated the absence of these NRs with alterations in the electroencephalographic signatures during sleep/awake periods.…”