Sex-regulated gene dosage effect of PPARα on synaptic plasticity

Mechanisms driving cognitive improvements following nuclear receptor activation are poorly understood. The peroxisome proliferator-activated nuclear receptor alpha (PPAR alpha) forms heterodimers with the nuclear retinoid X receptor (RXR). We report that PPAR alpha 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 PPAR alpha expression in males than in females, we show that male, but not female, PPAR alpha null mutants display impaired hippocampal long-term potentiation. Moreover, PPAR alpha knockdown in the hippocampus of cognition-impaired mice compromises the beneficial effects of RXR activation on synaptic plasticity only in males. Furthermore, selective PPAR alpha 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 PPAR alpha expression levels.