Identification et caractérisation de nouveaux outils moléculaires afin d'étudier la voie de la Polarité Cellulaire Planaire et son rôle dans la modulation de processus cognitifs

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 generalization. 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 signaling, either in adulthood or during normal and pathological aging, 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) signaling pathway. This signaling 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 signaling disrupts the structural organization of neurons in the dentate gyrus, which regulates specific cognitive processes such as pattern separation and pattern completion. We propose to characterize the role of C-Daam1 truncation – the C-terminal domain of the endogenous Daam1 protein belonging to PCP signaling – in specific brain functions. To do this, we combined molecular and cellular biology approaches with complex hippocampus-dependent behavioral 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 activity in both the dentate gyrus and CA3. Behaviorally, this translates into enhanced mnemonic discrimination (pattern separation) but impaired memory generalization (pattern completion). In addition, PCP signaling 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 modeling 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 aging.