AbstractsBiology & Animal Science

Long-lasting synaptic plasticity and memory storage rely on mRNA control mechanisms that allow for rapid changes in gene expression in response to synaptic activity. RNA-binding proteins, which affect the transport, stability and translational state of their target mRNAs, are an important component of these translational control mechanisms. Fragile X Related Protein 1 (FXR1P) is a member of the Fragile X family of RNA-binding proteins, which also includes Fragile X Mental Retardation Protein (FMRP) and Fragile X Related Protein 2 (FXR2P). FXR1P is known to both repress and enhance the translation of its target mRNAs in non-neuronal cells. However, its function in neurons is currently unknown. The central hypothesis of this thesis is that FXR1P controls the local translation of mRNAs important for spine development and synaptic plasticity in mice. To test this hypothesis, we used biochemical and confocal imaging techniques to study the expression pattern and subcellular localization of FXR1P in developing neurons and to look at the association of endogenous and exogenous FXR1P with the translational machinery. We then used a combination of confocal imaging, whole-cell electrophysiological recordings and two-photon glutamate uncaging approaches to measure the effect of increasing levels of FXR1P on spine number, spine morphology and spine function. Finally, we used a conditional mouse knockout approach to selectively delete FXR1P from postnatal forebrain neurons and studied the consequences of FXR1P loss on spine development and synaptic plasticity in adult mice. Interestingly, we found that FXR1P clustered with the translational machinery in dendrites and at a subset of large, functionally-strong dendritic spines. Genetic deletion of FXR1P decreased spine density and spine size and enhanced protein-synthesis dependent long-lasting long-term potentiation (L-LTP). Together, these results support the idea that FXR1P is positioned to control the local translation of a subset of mRNAs required for regulating the maintenance of spines and restraining the size of L-LTP. The results presented in this thesis expand on our understanding of the importance of translational control mechanisms in synaptic plasticity and cognition. La plasticité synaptique de longue durée et l'entreposage des mémoires nécessitent des mécanismes de contrôle de l'ARNm qui permettent des changements rapides dans l'expression des gènes en réponse à l'activité synaptique. Les protéines d'attachement à l'ARN sont une composante importante des mécanismes de contrôle de la traduction de l'ARNm. Ces protéines affectent le transport et la stabilité de leurs ARNm cible. La protéine reliée à Fragile X (FXR1P) est un membre de la famille Fragile X, des protéines d'attachement à l'ARN qui incluent FMRP et FXR2P. FXR1P est capable de réprimer et d'augmenter la traduction des ARNm cibles dans des lignées cellulaires non neuronales. Cependant, sa fonction dans les neurones demeure inconnue. L'hypothèse centrale de cette thèse est que FXR1P contrôle la traduction…