The anterior thalamic nuclei (ATN) are a critical part of an extended hippocampal system that supports key elements of episodic memory. Damage or disconnection of the ATN is a component of clinical conditions associated with severe anterograde amnesisa such as the Korsakoff’s syndrome, thalamic stroke, and neurodegenerative disorders. Previous studies have demonstrated that the ATN and hippocampus are often interdependent, and that ATN damage can result in ‘covert pathology’ in ostensibly healthy distal regions of the extended hippocampal system. Adult male rats with neurotoxic bilateral ATN lesions or sham surgery were post-operatively housed in an enriched environment or standard housing after a lesion-induced spatial working memory deficit had been established. These rats were retested on cross-maze and then trained in radial-arm maze spatial memory tasks. Other enriched rats received pseudo-training only after the enrichment period. The detailed neuromorphology of neurons was subsequently examined in the hippocampal CA1. Soma characteristics were also examined in the retrosplenial granular b cortex and the prelimbic cortex. In Experiment 1, ATN lesions produced clear deficits in both the cross-maze and radial-arm maze tasks and reduced hippocampal CA1 dendritic complexity, length, and spine density, while increasing the average diameter of the dendrites. Post-operative enrichment reversed the ATN lesion-induced deficits in the cross-maze and radial-arm maze, and returned CA1 basal and apical spine density to a level comparable to that of sham standard housed trained rats. The sham enriched rats exhibited improved radial-arm maze performance and increased CA1 branching complexity and spine density in both basal and apical arbors compared to sham standard housed rats. The neuromorphological changes observed in the enriched ATN and sham rats may be in part responsible for the spatial working memory improvements observed. Experiment 2 provided support for this contention by demonstrating that the CA1 spine changes were explicitly relevant to spatial learning and memory, because trained enriched sham and ATN rats had increased spines, particularly in the basal tree when compared to closely comparable pseudo-trained enriched rats. Interestingly, spatial memory training increased the numbers of both thin and mushroom spines, whereas enrichment was only associated with an increase in thin spines. In Experiment 3, ATN lesions increased cell body size in layer II of the retrosplenial granular b cortex, whereas enrichment decreased cell body size in layer V of this region. Neither ATN lesions nor enrichment had any effect on cell body morphology in the prelimbic cortex. The current research provides some of the strongest evidence to date of ATN and hippocampal interdependence within the extended hippocampal system, and provides the first evidence of neuromorphological correlates of recovery after ATN lesions.

Alix (ALG-2 Interacting Protein X) est une protéine cytoplasmique impliquée dans divers processus cellulaires allant de l'apoptose à la cytocinèse en passant par le bourgeonnement des virus, la réparation membranaire et la régulation de la voie endosomale. Toutes ces fonctions sont étroitement associées à l'interaction d'Alix avec ses partenaires impliqués dans la déformation des membranes telles que les endophilines A, Tsg-101 et CHMP4B du complexe ESCRT (Endosomal Sorting Complex Required for Transport). Le but de ce projet est de caractériser le phénotype de la souris Alix ko récemment développée au laboratoire, dans l'espoir de mieux comprendre le rôle physiologique d'Alix. Ces souris, viables et fertiles, sont caractérisées par une microcéphalie apparaissant au cours de l'embryogenèse. Ce phénotype est accompagné d'une apoptose massive touchant les progéniteurs neuronaux durant la neurogenèse et d'une altération du développement de l'arborisation dendritique après la naissance. Les souris adultes présentent également des défauts de plasticité synaptique accompagnés d'une altération du recyclage des vésicules synaptiques. L'ensemble de ces processus repose sur la capacité d'Alix à contrôler le remodelage de la membrane plasmique. Au niveau moléculaire, nos travaux sur les neurones en cultures et sur les fibroblastes montrent une régulation de l'endocytose indépendante de la clathrine (CIE) par Alix et les endophilines A qui pourrait être à l'origine du phénotype neuronal de la souris. Cependant, l'association d'Alix avec CHMP4B du complexe ESCRT pourrait également être nécessaire au développement du système nerveux puisque l'interaction Alix-CHMP4B est nécessaire pour le contrôle de la CIE et de la mort neuronale.L'ensemble de ces résultats mets en évidence qu'à travers des mécanismes et des partenaires bien caractérisés, Alix est requise pour de nouvelles fonctions nécessaires au développement et au fonctionnement du système nerveux. / Alix (ALG-2 Interacting Protein X) is a cytoplasmic protein implicated in multiple processes including apoptosis, endosome function, membrane repair, viral budding and cytokinesis. Most of these involve modifications of plasma or endosomal membrane organization. Consistent with this, Alix is known to interact with diverse proteins modulating membrane deformation, such as endophilins or Tsg-101 and CHMP4B of the Endosomal Sorting Complex Required for Transport (ESCRT). By studying the phenotype of Alix ko mice that we recently developed, we aim to better understand the precise role of Alix in vivo. These mice are viable and fertile but develop microcephaly even at embryonic stages. This microcephaly is associated with an increase of apoptosis in neural progenitor cells in embryos and a defect in neurite outgrowth at post-natal stages. Later on, these mice also develop defects in synaptic plasticity related to an alteration of synaptic vesicle recycling. All of these processes are tightly dependent on membrane shaping and remodelling. These features of the phenotype can be related to a new function of Alix with endophilin A in the control of clathrin-independent endocytosis (CIE), as described in Alix ko fibroblasts and cultured neurons. However, these defects might also be related to the well-known Alix partner CHMP4B, since we now know that this interaction is needed for controlling CIE and neuronal cell death.All together, these results shed light on novel functions of Alix in the developing and adult central nervous system, all relying on well-known molecular mechanisms and partners.