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Rôle du transporteur vésiculaire du glutamate de type 3 (VGLUT3) dans la réponse au stress hypoxique néonatal et la surdité DFNA25

Abstract : Before its release into synaptic cleft, glutamate is accumulated in presynaptic vesicles by vesicular glutamate transporters (VGLUTs). There are 3 types of VGLUTs. VGLUT3 presents atypical functions and anatomical distribution. In the central nervous system, VGLUT3 is expressed in glutamatergic and non glutamatergic neurons, in which it performs the co-transmission and the vesicular synergy. Particularly, we can observe VGLUT3 in serotoninergic neurons of raphe. In the inner ear, VGLUT3 is the unique VGLUT described in the inner hair cells (IHCs). Serotonin plays a key role in the neonatal respiratory control. By exploring the respiration of VGLUT3 knock out mice pumps, we have demonstrated the role of VGLUT3 in the response to neonatal hypoxic stress. One VGLUT3 mutation has been described in a human deafness clinically very close to presbycusis, the DFNA25 deafness. By studying the auditory phenotype of mice expressing this VGLUT3 mutation, we have proved the implication of this mutation in the IHCs impairment at the origin of DFNA25 deafness. Biochemical analysis have helped us to consider an indirect role of VGLUT3 in the autophagic death. Beclin 1 and a possible interaction between VGLUT3 and the Cullin3 pathways could be implicated. All of our results allowed us to highlight a role of VGLUT3 in the adaptation to extreme conditions like neonatal development or aging process. They open new perspectives on the various functions of VGLUTs.
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Stéphanie Miot. Rôle du transporteur vésiculaire du glutamate de type 3 (VGLUT3) dans la réponse au stress hypoxique néonatal et la surdité DFNA25. Neurosciences [q-bio.NC]. Université Pierre et Marie Curie - Paris VI, 2017. Français. ⟨NNT : 2017PA066011⟩. ⟨tel-02048943⟩

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