Venue : Centre Broca
Éloïse Daniel
Team : Planar polarity and plasticity
Neurocentre Magendie
Lieu : Centre Broca
Éloïse Daniel
Équipe : Polarité planaire et plasticité (Sans)
Neurocentre Magendie
Title
Identification and characterisation of new molecular tools to study the Planar Cell Polarity signalling and its role in cognitive processes
Abstract
A good memory is not just about correctly recalling learned information, but also about encoding memories distinctly from one another and being able to retrieve a complete memory from partial information. These two cognitive processes are pattern separation – or memory discrimination – and pattern completion – or memory generalisation. Both rely on the hippocampus, a brain structure that is crucial for learning, consolidating, and recalling memories. To accomplish these complex tasks, the hippocampus relies on the trisynaptic circuit composed of the entorhinal cortex, the dentate gyrus, and the CA3 region of the hippocampus. These structures can be compromised by alterations in intra- and intercellular signalling, either in adulthood or during normal and pathological ageing, or during the maturation of neural circuits. Numerous studies have shown that receptors, adhesion molecules, or scaffolding proteins may play a role in these memory processes.
Among these genes and proteins are members of the planar cell polarity (PCP) signalling pathway. This signalling pathway is conserved and known to shape tissues during development by regulating adhesion complexes and cytoskeletal dynamics. In this project, we are testing the hypothesis that modulation of PCP signalling disrupts the structural organisation of neurons in the dentate gyrus, which regulates specific cognitive processes such as pattern separation and pattern completion. We propose to characterise the role of C-Daam1 truncation – the C-terminal domain of the endogenous Daam1 protein belonging to PCP signalling – in specific brain functions. To do this, we combined molecular and cellular biology approaches with complex hippocampus-dependent behavioural tasks designed to capture the properties and elementary components of declarative memory in animals.
Our results show that overexpression of C-Daam1 in adult mice reduces the dendritic complexity of granule cells in the dentate gyrus and neuronal activation in both the dentate gyrus and CA3. Behaviourally, this translates into enhanced mnemonic discrimination (pattern separation) but impaired memory generalisation (pattern completion). In addition, PCP signalling dependent on Daam1 has recently been associated with synaptic dysfunction induced by β-amyloid accumulation, a protein directly involved in Alzheimer’s disease. We therefore evaluated the potential effect of C-Daam1 in transgenic mice modelling this pathology. Strikingly, C-Daam1 enables long-term memory maintenance in the early stages of the disease.
This project provides new insights into the mechanisms supporting functional memory and opens up new therapeutic avenues for maintaining mnemonic abilities during pathological ageing.
Keywords: Hippocampus, Memory, Planar Cell Polarity
Publications
Non publié
Daniel E.L.J., Moreau M., Houguet A., Isch C., Poirault-chassac S., Depret N., Montcouquiol M., Desmedt A., Marighetto A., Sans N.
‘Modulation of the PCP signaling pathway regulates mnemonic discrimination and pattern completion processes in mice’. (in preparation)
Sélection
Benjamin J. A. Robert and others, ‘Vangl2 in the Dentate Network Modulates Pattern Separation and Pattern Completion’, Cell Reports, 31.10 (2020), p. 107743, doi:10.1016/j.celrep.2020.107743.
Habas et al., ‘Wnt/Frizzled Activation of Rho Regulates Vertebrate Gastrulation and Requires a Novel Formin Homology Protein Daam1’, Cell 107, no. 7 (2001): 843–54, https://doi.org/10.1016/s0092-8674(01)00614-6.
Katherine J. Sellers et al., ‘Amyloid β Synaptotoxicity Is Wnt-PCP Dependent and Blocked by Fasudil’, Alzheimer’s & Dementia 14, no. 3 (2018): 306–17, https://doi.org/10.1016/j.jalz.2017.09.008.
Jury
Dr RAMPON Claire Université de Toulouse Rapportrice
Dr POIRIER Roseline Université de Paris-Saclay Rapportrice
Dr PIETROPAOLO Susanna Université de Bordeaux Examinatrice
Dr WOLFF Mathieu Université de Bordeaux Examinateur
Dr SANS Nathalie Université de Bordeaux Directrice de thèse (membre invité)
Dr MARIGHETTO Aline Université de Bordeaux Membre invité