| First Author | Pierrot N | Year | 2019 |
| Journal | Life Sci Alliance | Volume | 2 |
| Issue | 2 | PubMed ID | 30894406 |
| Mgi Jnum | J:284813 | Mgi Id | MGI:6391938 |
| Doi | 10.26508/lsa.201800262 | Citation | Pierrot N, et al. (2019) Sex-regulated gene dosage effect of PPARalpha on synaptic plasticity. Life Sci Alliance 2(2) |
| abstractText | Mechanisms driving cognitive improvements following nuclear receptor activation are poorly understood. The peroxisome proliferator-activated nuclear receptor alpha (PPARalpha) forms heterodimers with the nuclear retinoid X receptor (RXR). We report that PPARalpha 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 PPARalpha expression in males than in females, we show that male, but not female, PPARalpha null mutants display impaired hippocampal long-term potentiation. Moreover, PPARalpha knockdown in the hippocampus of cognition-impaired mice compromises the beneficial effects of RXR activation on synaptic plasticity only in males. Furthermore, selective PPARalpha 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 PPARalpha expression levels. |
