Sex-regulated gene dosage effect of PPARα on synaptic plasticity.
Animals
Benzoxazoles
/ pharmacology
Butyrates
/ pharmacology
Cells, Cultured
Cognitive Dysfunction
/ genetics
Female
Gene Dosage
/ genetics
Gene Knockdown Techniques
Hippocampus
/ cytology
Long-Term Potentiation
/ drug effects
Male
Mice
Mice, Transgenic
Neuronal Plasticity
/ genetics
PPAR alpha
/ agonists
Rats
Rats, Wistar
Receptors, AMPA
/ metabolism
Retinoid X Receptors
/ metabolism
Sex Factors
Signal Transduction
/ drug effects
Journal
Life science alliance
ISSN: 2575-1077
Titre abrégé: Life Sci Alliance
Pays: United States
ID NLM: 101728869
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
30
11
2018
revised:
01
03
2019
accepted:
11
03
2019
entrez:
22
3
2019
pubmed:
22
3
2019
medline:
22
3
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 30894406
pii: 2/2/e201800262
doi: 10.26508/lsa.201800262
pmc: PMC6427998
pii:
doi:
Substances chimiques
(R)-2-(3-((benzoxazol-2-yl-d4 (3-(4-methoxyphenoxy-d7)propyl)amino)methyl)phenoxy) butanoic acid
0
Benzoxazoles
0
Butyrates
0
PPAR alpha
0
Ppara protein, mouse
0
Receptors, AMPA
0
Retinoid X Receptors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2019 Pierrot et al.
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