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Sex-regulated gene dosage effect of PPAR? on synaptic plasticity.

ABSTRACT: Mechanisms driving cognitive improvements following nuclear receptor activation are poorly understood. The peroxisome proliferator-activated nuclear receptor alpha (PPAR?) forms heterodimers with the nuclear retinoid X receptor (RXR). We report that PPAR? 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 PPAR? expression in males than in females, we show that male, but not female, PPAR? null mutants display impaired hippocampal long-term potentiation. Moreover, PPAR? knockdown in the hippocampus of cognition-impaired mice compromises the beneficial effects of RXR activation on synaptic plasticity only in males. Furthermore, selective PPAR? 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 PPAR? expression levels.

SUBMITTER: Pierrot N

PROVIDER: S-EPMC6427998 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Sex-regulated gene dosage effect of PPARα on synaptic plasticity.

Pierrot Nathalie N Ris Laurence L Stancu Ilie-Cosmin IC Doshina Anna A Ribeiro Floriane F Tyteca Donatienne D Baugé Eric E Lalloyer Fanny F Malong Liza L Schakman Olivier O Leroy Karelle K Kienlen-Campard Pascal P Gailly Philippe P Brion Jean-Pierre JP Dewachter Ilse I Staels Bart B Octave Jean-Noël JN

Life science alliance 20190320 2

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-i ...[more]

PMID: 30894406

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Sex-regulated gene dosage effect of PPAR? on synaptic plasticity.

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Sex-regulated gene dosage effect of PPARα on synaptic plasticity.

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