Rôle de la signalisation de la polarité cellulaire planaire dans les processus mnésiques
Rôle de la signalisation de la polarité cellulaire planaire dans les processus mnésiques.
Thèse soutenue le 4 décembre 2017
Sous la direction de Nathalie Sans / Neurocentre Magendie / Team : Polarité planaire et plasticité.
Vangl2 is a planar polarity protein involved in many embryonic developmental mechanisms in mammals, but its specific role in brain maturation remains unknown. Results from our group show that Vangl2 is enriched in the hippocampus of developing and adult mice; notably in dentate gyrus (DG)/CA3 network. This network is crucial for two specific cognitive processes called ‘pattern completion’ (PC) and ‘pattern separation’ (PS). PC is described as the ability to guide the recall of an entire memory using partial sensory cues. PS allows encoding similar inputs, like a ‘separator’, and transmitting the information in a distinct manner.
Based on these observations, we hypothesized that Vangl2 play a role in these adult hippocampal cognitive processes. For this purpose, (i) we first generated and characterized conditional mutant mice with region-specific loss of vangl2. (ii) Next, I evaluated the cognitive consequences of the deletion of vangl2 in these mice using specific behavioral tasks requiring PC and PS. (iii) Finally, I performed histological and biochemical analyses on mutant mice to understand the mechanisms of action of Vangl2 in the DG/CA3 network.
(i) Because of the importance of Vangl2 in many developmental processes, we had to develop conditional mutants to delete vangl2 after birth and in postmitotic neurons of the hippocampus. Using Cre-lox system by breeding mutant mice lines or using stereotaxic lentiviral injection I was able to downregulate Vangl2 protein in the adult hippocampus.
(ii) To assess the ability of mice to use PC, I used a Morris water maze task and results suggest that vangl2 mutants are impaired to rebuild the spatial map from partial cues to locate the platform. Moreover, the same mutants performed better in a contextual discrimination task, that relies on the use of PS, suggesting that Vangl2 regulate a balance that could exist between PC and PS.
(iii) Recent studies reveal that DG, known to be essential for PS, also plays a crucial role in PC depending of the maturation of the DG granule cells. Using immunohistochemistry, I showed that proportion of immature neurons is increased in vangl2 mutant mice compared to controls. Moreover dendritic arborization and spine maturation, two components that reflect neurons maturation are impaired in dentate gyrus granule cells in vangl2 mutants.
Altogether my results showed that the planar polarity protein Vangl2 is involved in the maturation process of dentate gyrus granule cells, and modulate two specific cognitive processes depending on DG-CA3 connectivity, the pattern completion and the pattern separation.
Keywords: Vangl2, planar cell polarity, plasticity, memory, pattern separation, pattern completion, LTP
Robert BJA et al., Montcouquiol M & Sans N. Vangl2 fine-tunes hippocampal-dependent context discrimination and spatial completion. In prep.
Moreau M, Pietropaolo S*, Ezan J*, Robert BJA, Miraux S, Maître M, Cho Y, Crusio W, Montcouquiol M* & Sans N*. Blockage of the ERK-Mnk1 dependent pathway improves social communication in a mice model of neurodevelopmental disorder. In review.
Dos-Santos Carvalho S*, Quiedeville A*, Moreau MM*, Stockton J, Al-Abed S, Decroo M, Peyroutou R, Robert BJA, Racca C, Marighetto A, Sans N & Montcouquiol M. Vangl2 controls the morphofunctional development of the DG-CA3 network of the hippocampus. In prep.
Bruno BONTEMPI Université de Bordeaux, Président
Claire RAMPON Université de Toulouse, Rapportrice
Fadel TISSIR Université de Louvain (Belgique), Rapporteur
Valérie CREPEL Université de Marseille, Examinatrice
Pierre TRIFILIEFF Université de Bordeaux, Examinateur
Nathalie SANS, Université de Bordeaux, Directrice de thèse