The Scrib1 Interactome and its relevance for synaptic plasticity & neurodevelopmental disorders
Defended on December 4, 2014
The brain is made up of billions of nerve cells, or neurons. Neurons communicate with each other through functionally distinct structures – the axon and the dendrite – which are able to release and receive an electrical or chemical signal from a pre- to a post-synaptic compartment, respectively. We focused our study on hippocampal neurons synapses, which ultimately underlie high-order brain functions, such as learning and memory. In particular, we studied the development and maintenance of dendritic spines, whose changes in morphology are intimately correlated with synaptic plasticity, or the ability to respond to synaptic activity.
Dendritic spines originate from motile dendritic filopodia, which mature into spines following axonal contact. The filopodia-to-spine transition involves a plethora of molecular actors, including glutamate receptors, scaffold proteins and the actin cytoskeleton, able to receive, transmit and integrate the pre-synaptic signal. The spatial and temporal coordination of all these molecular components throughout the formation and maturation of a synapse remains, however, unclear. Scribble1 (Scrib1) is planar cell polarity protein (PCP) classically implicated in the homeostasis of epithelial tissues and tumour growth. In the mammalian brain, Scrib1 is a critical scaffold protein in brain development and function.
The main goal of this work was, therefore, to investigate the molecular mechanisms underlying Scrib1 role in synapse formation and maintenance. In a first part, the functional consequences of a recently identified autism spectrum disorder (ASD) mutation of Scrib1 on neuronal morpholgy and function. We demonstrated that Scrib1 regulates dendritic arborization as well as dendritic spine formation and functional maintenance via an actin-dependent mechanism, whose disruption might underlie the ASD phenotype. In a second part, we depict the importance of Scrib1 PDZ-dependent interactions on glutamate receptors trafficking as well as bidirectional plasticity signalling pathway underying spatial memory.
Taken altogether, this thesis highlights the PCP protein Scrib1 as key scaffold protein in brain development and function, playing a plethora of roles from the subcelular to the cognitive level.
Keywords: Scrib1, autism spectrum disorders, hippocampal neurons, synaptic plasticity, dendritic spine, glutamate receptors traffic, actin dynamics.
Piguel NH, Fievre S, Blanc JM, Carta M, Moreau MM, Moutin E, Pinheiro VL, Medina C, Ezan J, Lasvaux L, Loll F, Durand CM, Chang K, Petralia RS, Wenthold RJ, Stephenson FA, Vuillard L, Darbon H, Perroy J, Mulle C, Montcouquiol M, Racca C & Sans N. Scribble1/AP-2 complex coordinates NMDA receptor endocytic recycling. Cell Reports 9, 1–16, October 23, 2014;
Hilal M, Moreau MM, Racca C, Pinheiro VL, Santoni MJ, Carvalho SS, Piguel NH, Rachel R, Abada YS, Blanc JM, Medina C, Doat H, Papouin T, Panatier A, Borg JP, Montcouquiol M, Oliet SHR & Sans N. Scribble 1 scaffolds protein phosphatases 1 and 2A to regulate bidirectional plasticity underlying spatial memory. In preparation;
Pinheiro VL, Mehidi A, Piguel NH, Fanet H, Medina C et al. & Sans N. Disrupting Scrib1-mediated actin regulation impacts neuronal complexity, synapse formation and maintenance. In preparation; Pinheiro, VL, Racca C & Sans N. Reviewing AMPA receptor trafficking – The Who, What, Why, When, Where & How. In preparation.
- Dr. Maurice GARRET
Bordeaux, France- Chairman
- Prof. Ana Luisa Carvalho
Coimbra, Portugal – Reviewer
- Prof. Jeremy HENLEY
Bristol, United Kingdom – Reviewer
- Dr. Olivier Thoumine
Bordeaux, France – Examiner
- Prof. Jean Paul BORG
Marseille, France – Examiner
- Dr. Nathalie SANS
Bordeaux, France – Thesis supervisor
Nathalie SANS, Ph.D.
Associate team leader: Planar Polarity and Plasticity
Neurocentre Magendie, INSERM U862. Université de Bordeaux