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

par Pierrot, Nathalie;Ris, Laurence ;Stancu, Ilie-Cosmin;Doshina, Anna;Ribeiro, Floriane;Tyteca, Donatienne;Baugé, Eric;Lalloyer, Fanny;Malong, Liza;Schakman, Olivier;Leroy, Karelle ;Kienlen-Campard, Pascal Kienlen;Gailly, Philippe;Brion, Jean Pierre ;Dewachter, Ilse;Staels, Bart;Octave, Jean Noël
Référence Life science alliance, 2, 2
Publication Publié, 2019-04

Article révisé par les pairs

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Résumé :

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.