Sex-regulated gene dosage effect of PPARα on synaptic plasticity

  • Life Sci Alliance. 2019 Mar 20;2(2):e201800262. doi: 10.26508/lsa.201800262.
Nathalie Pierrot  1  2 ,  Laurence Ris  3 ,  Ilie-Cosmin Stancu  4  2  5 ,  Anna Doshina  4  2 ,  Floriane Ribeiro  4  2 ,  Donatienne Tyteca  4  6 ,  Eric Baugé  7 ,  Fanny Lalloyer  7 ,  Liza Malong  4  2 ,  Olivier Schakman  4  2 ,  Karelle Leroy  8 ,  Pascal Kienlen-Campard  4  2 ,  Philippe Gailly  4  2 ,  Jean-Pierre Brion  8 ,  Ilse Dewachter  4  2  5 ,  Bart Staels  7 ,  Jean-Noël Octave  4  2
Affiliations
  • 1. Université Catholique de Louvain, Brussels, Belgium [email protected].
  • 2. Institute of Neuroscience, Brussels, Belgium.
  • 3. Laboratory of Neuroscience, Health Institute, University of Mons, Mons, Belgium.
  • 4. Université Catholique de Louvain, Brussels, Belgium.
  • 5. Biomedical Research Institute, Hasselt University, Hasselt, Belgium.
  • 6. de Duve Institute, Brussels, Belgium.
  • 7. Université de Lille EGID, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, France.
  • 8. Laboratory of Histology and Neuropathology, Université Libre de Bruxelles, Brussels, Belgium.
PMID: 30894406 DOI: 10.26508/lsa.201800262
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.

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