Abstract
Mechanisms driving cognitive improvements following nuclear receptor activation are poorly understood. The peroxisome proliferator-activated nuclear receptor alpha (PPARα) forms heterodimers with the nuclear retinoid X receptor (RXR). We report that PPARα mediates the improvement of hippocampal synaptic plasticity upon RXR activation in a transgenic mouse model with cognitive deficits. This improvement results from an increase in GluA1 subunit expression of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, eliciting an AMPA response at the excitatory synapses. Associated with a two times higher PPARα expression in males than in females, we show that male, but not female, PPARα null mutants display impaired hippocampal long-term potentiation. Moreover, PPARα knockdown in the hippocampus of cognition-impaired mice compromises the beneficial effects of RXR activation on synaptic plasticity only in males. Furthermore, selective PPARα activation with pemafibrate improves synaptic plasticity in male cognition-impaired mice, but not in females. We conclude that striking sex differences in hippocampal synaptic plasticity are observed in mice, related to differences in PPARα expression levels.
Highlights
The nuclear receptor (NR) superfamily of ligand-dependent transcription factors are broadly implicated in a wide variety of biological processes regulating energy balance, inflammation, lipid, and glucose metabolism (Evans & Mangelsdorf, 2014)
We report here that PPARα, a master metabolic regulator involved in fatty acid (FA) catabolism (Staels et al, 1998), plays a central role in hippocampal synaptic plasticity by driving the expression of the GluA1 subunit of AMPA receptors (AMPARs) in a sex-specific manner
We show that long-term potentiation (LTP) improvement observed in a Tg mouse model of Alzheimer’s disease (AD) upon retinoid X receptor (RXR) activation with bexarotene is concomitant with the specific up-regulation of GluA1 expression
Summary
The nuclear receptor (NR) superfamily of ligand-dependent transcription factors are broadly implicated in a wide variety of biological processes regulating energy balance, inflammation, lipid, and glucose metabolism (Evans & Mangelsdorf, 2014). NRs play an important role in the adaptive responses to environmental changes by controlling directly the expression of target genes through binding to sequence-specific elements located in gene regulatory regions (Evans & Mangelsdorf, 2014). PPAR/RXR and LXR/RXR heterodimers are permissive, meaning that receptor dimers can be activated by ligands for either partner in the dimer, or even by both synergistically (Evans & Mangelsdorf, 2014). PPARs, including PPARα, PPARβ/δ, and PPARγ, are master metabolic regulators in response to dietary changes. PPARs and LXRs have anti-inflammatory effects because they repress transcription of genes encoding pro-inflammatory cytokines (reviewed in Bensinger & Tontonoz (2008))
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