CEMO monthly seminar - Nathalie Pierrot

CEMO is delighted to announce the seminars of the department that will be given by PhD student and Postdoc.

The seminar is followed by a lunch (kindly provided by the department) in order to allow everybody to interact and promote collaboration between labs.

Agenda:

12:00 - Nathalie Pierrot (Alzheimer dementia group): "Gender specific improvement of synaptic function by activation of RXR nuclear receptor is mediated by PPAR"

Pierrot^1,2, Laurence Ris³, Ilie-Cosmin Stancu^1,2,4, Anna Doshina^1,2, Floriane Ribeiro^1,2, Donatienne Tyteca^1,5, Eric Baugé⁶, Fanny Lalloyer⁶, Liza Malong^1,2, Olivier Schakman^1,2, Karelle Leroy⁷, Pascal Kienlen-Campard^1,2, Philippe Gailly^1,2, Jean-Pierre Brion⁷, Ilse Dewachter^1,2,4, Bart Staels⁶ and Jean-Noël Octave^1,2.

¹ Université catholique de Louvain, B-1200 Brussels, Belgium
² Institute of Neuroscience, B-1200 Brussels, Belgium
³ Laboratory of Neuroscience, Health Institute, University of Mons, B-7000, Mons, Belgium
⁴ Biomedical Research Institute, Hasselt University, 3500 Hasselt, Belgium
⁵ de Duve Institute, B-1200 Brussels, Belgium
⁶ Université de Lille EGID, Inserm, CHU Lille, Institut Pasteur de Lille, U1011, F-59000 Lille, France
⁷ Laboratory of Histology and Neuropathology, Université libre de Bruxelles, 1070 Brussels, Belgium

Abstract:

Objectives:

Nuclear receptors (NRs) are ligand-dependent transcription factors regulating gene expression. Among NRs, peroxisome proliferator-activated receptor (PPAR) forms permissive obligate heterodimers with retinoid X receptor (RXR). NRs activation with specific agonists leads to brain function improvement in mouse models of neurodegenerative diseases. However, the link between NRs activation and cognitive improvement is missing. Here, we analyzed how RXR activation improves synaptic plasticity and neuronal function and identified PPARa as a crucial player.

Methods:

LTP was measured in the hippocampus of PPARa null mice and in a mouse model of Alzheimer’s disease (5xFAD) treated with the RXR agonist bexarotene or with pemafibrate, a selective PPARα activator. PPARa expression was acutely decreased in the hippocampus of 5xFAD mice by using an AAV-ShPpara. Glutamatergic responses were measured by calcium imaging in rat primary cortical cultures. NMDA and AMPA receptors subunits expression were assessed by RT-qPCR and western blotting.

Results:

Upon RXR activation, the PPARa-dependent upregulation of the GluA1 subunit-containing AMPA receptors mediates LTP improvement in 5xFAD mice and AMPA-responses in cortical cells. PPARa deficiency severely impaired LTP and GluA1 expression in male but not in female PPARa null mice. PPARa-knockdown in the hippocampus of 5xFAD mice compromises the beneficial effects of RXR activation on synaptic plasticity only in males. PPARa activation with pemafibrate improves synaptic plasticity in male 5xFAD mice, but not in females.

Conclusions:

PPARa plays a central role in hippocampal synaptic plasticity by driving the expression of GluA1 subunit of AMPARs in a gender specific manner.

12:45 - Q&A session

13:00 - Lunch