PT - JOURNAL ARTICLE AU - Nathalie Pierrot AU - Laurence Ris AU - Ilie-Cosmin Stancu AU - Anna Doshina AU - Floriane Ribeiro AU - Donatienne Tyteca AU - Eric Baugé AU - Fanny Lalloyer AU - Liza Malong AU - Olivier Schakman AU - Karelle Leroy AU - Pascal Kienlen-Campard AU - Philippe Gailly AU - Jean-Pierre Brion AU - Ilse Dewachter AU - Bart Staels AU - Jean-Noël Octave TI - Sex-regulated gene dosage effect of PPARα on synaptic plasticity AID - 10.26508/lsa.201800262 DP - 2019 Apr 01 TA - Life Science Alliance PG - e201800262 VI - 2 IP - 2 4099 - https://www.life-science-alliance.org/content/2/2/e201800262.short 4100 - https://www.life-science-alliance.org/content/2/2/e201800262.full SO - Life Sci. Alliance2019 Apr 01; 2 AB - 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.