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PhD Position: Presynaptic plasticity and memory in the context of Fragile X

Thesis Director: Christophe Mulle

Lab:
Interdisciplinary Institute of Neuroscience,
CNRS UMR 5297
University of Bordeaux

Starting Date: September 2021

3-years PhD contract fully funded through an ANR grant

Contact:

Title of Project:

Presynaptic plasticity and memory in the context of Fragile X

Summary of thesis project

Fragile X Syndrome (FXS) is the most frequent form of inherited intellectual disability (ID) and a leading cause of autism spectrum disorder (ASD). FXS is caused by the silencing of the Fragile X Mental Retardation gene (FMR1) which encodes the RNA-binding protein FMRP. Fmr1-KO mice recapitulate the disorder and are  a model of both ID and ASD. The project, which is part of a national collaboration (ANR NotifX), aims at characterizing the functional implication of novel targets of FMRP. Here we focus on targets which could play a role in presynaptic forms of synaptic plasticity, with a primary focus on a recently identified target, Phosphodiesterase 2A (PDE2A). Most studies in the context of FXS have related to dendritic and post synaptic mechanisms. However, PDE2A is located in docked synaptic vesicles and highly expressed in brain regions involved in FXS pathology.

The role of PDE2A in functional and structural presynaptic mechanisms needs to be further explored in Fmr1-KO. The specific aim of the project is to unravel the impact of dysregulated PDE2A induced by the absence of FMRP on structural and functional presynaptic mechanisms and plasticity in the CA3 region of the hippocampus. Here we will test whether presynaptic mechanisms and plasticity are altered in Fmr1-KO mice. In addition, correction of phenotypes (if any) driven by the absence of FMRP, will be carried out by reducing the expression level or activity of PDE2A.

Methodology

The project will use a combination of patch-clamp electrophysiology and 2-photon imaging in slices with behaviour, in mice with cell-specific gene mutations targeted to the dentate gyrus and CA3.

We are seeking for :

A candidate with a strong background in cellular neuroscience, and interest in the analysis of synapses and circuits in the context of a memory-related brain disorder.

Selected recent publications of the team

  • Viana da Silva, S., Haberl, M.G., Zhang, P., Bethge, P., Lemos, C., Gonçalves, N., Gorlewicz, A., Malezieux, M., Gonçalves, F.Q., Grosjean, N., Blanchet, C., Frick, A., Nägerl, U.V., Cunha, R.A., Mulle, C., 2016. Early synaptic deficits in the APP/PS1 mouse model of Alzheimer’s disease involve neuronal adenosine A2A receptors. Nature Communications 7, 11915.
  • Fievre, S., Carta, M., Chamma, I., Labrousse, V., Thoumine, O., Mulle, C., 2016. Molecular determinants for the strictly compartmentalized expression of kainate receptors in CA3 pyramidal cells. Nature Communications 7, 12738.
  • Zucca, S., Griguoli, M., Malezieux, M., Grosjean, N., Carta, M., Mulle, C., 2017. Control of Spike Transfer at Hippocampal Mossy Fiber Synapses In Vivo by GABAA and GABAB Receptor-Mediated Inhibition. Journal of Neuroscience 37, 587–598.
  • Rebola, N., Carta, M., Mulle, C., 2017. Operation and plasticity of hippocampal CA3 circuits: implications for memory encoding. Nat Rev Neurosci 18, 209–221.
  • Barthet, G., Jordà-Siquier, T., Rumi-Masante, J., Bernadou, F., Müller, U., Mulle, C., 2018. Presenilin-mediated cleavage of APP regulates synaptotagmin-7 and presynaptic plasticity. Nature Communications 1–14. doi:10.1038/s41467-018-06813-x
  • Carta, M., Srikumar, B.N., Gorlewicz, A., Rebola, N., Mulle, C., 2018. Activity-dependent control of NMDA receptor subunit composition at hippocampal mossy fibre synapses. J Physiol (Lond) 596, 703–716.
  • Viana da Silva, S., Zhang, P., Georg Haberl, M., Labrousse, V., Grosjean, N., Blanchet, C., Frick, A., Mulle, C., 2019. Hippocampal mossy fibers synapses in CA3 pyramidal cells are altered at an early stage in a mouse model of Alzheimer’s disease. Journal of Neuroscience 2868–18–13.
  • Malezieux, M., Kees, A.L., Mulle, C., 2020. Theta Oscillations Coincide with Sustained Hyperpolarization in CA3 Pyramidal Cells, Underlying Decreased Firing. CellReports 32, 107868.
  • Barthet, G., Mulle, C., 2020. Presynaptic failure in Alzheimer’s disease. Prog Neurobiol 101801.

 

30/04/21