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Interactions neurogliales dans la déficience intellectuelle : étude du modèle oligophrénine-1

Abstract : The synapse mediates the inter-neuron communication that forms the basis of all cognitive activity. Mutations in genes encoding for synaptic proteins are responsible for neurodevelopmental disorders called synaptopathies, covering a large clinical spectrum from intellectual disability (ID) to autism spectrum disorders. However it is currently established that neurons are not the only active cells at the synapse. Astrocytes play as well an essential role for its development and functioning. They maintain synaptic ionic homeostasis and are capable of secreting gliotransmitters, which can modulate synaptic activity. Oligophrenin-1 gene (OPHN1) was identified and associated with X-linked human ID. OPHN1 is a synaptic protein, which neuronal function is well known. It can directly interact with the actin-cytoskeleton and plays a role in the formation and maturation of dendritic spines. This protein is also expressed in astrocytes but its astrocytic function is still unknown. Using the Ophn1 KO mouse model, we were able to highlight in vitro the consequences induced by its deletion in astrocytes. We demonstrated that the absence of OPHN1 disturbed astrocytic migration and morphology in vitro. Since Ophn1 negatively regulates RhoA GTPase, we used an inhibitor of the RhoA/ROCK pathway to rescue the phenotype back to control. In vivo we took advantage of the cortical glial scar formation to observ astrocytic migration and morphology in KO mice. We found that Ophn1 deletion disrupted glial scar formation and that astrocytes near the wound were less ramified. Taken together, these results show that astrocytes are altered in our mouse model of X-linked ID. Moreover the development of an astrocytic conditional KO for Ophn1 will allow us to study the consequences of astrocytic loss of OPHN1 and determine the astrocytic contribution in the pathophysiology of this neurodevelopmental disease.
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Laure-Elise Pillet. Interactions neurogliales dans la déficience intellectuelle : étude du modèle oligophrénine-1. Neurobiologie. Université Sorbonne Paris Cité, 2018. Français. ⟨NNT : 2018USPCB246⟩. ⟨tel-02527909⟩

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