RT Journal Article
SR Electronic
T1 Sex-regulated gene dosage effect of PPARα on synaptic plasticity
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201800262
DO 10.26508/lsa.201800262
VO 2
IS 2
A1 Nathalie Pierrot
A1 Laurence Ris
A1 Ilie-Cosmin Stancu
A1 Anna Doshina
A1 Floriane Ribeiro
A1 Donatienne Tyteca
A1 Eric Baugé
A1 Fanny Lalloyer
A1 Liza Malong
A1 Olivier Schakman
A1 Karelle Leroy
A1 Pascal Kienlen-Campard
A1 Philippe Gailly
A1 Jean-Pierre Brion
A1 Ilse Dewachter
A1 Bart Staels
A1 Jean-Noël Octave
YR 2019
UL https://www.life-science-alliance.org/content/2/2/e201800262.abstract
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.