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Reference : UMR7275-MASMAN-003
Workplace : VALBONNE
Date of publication : Thursday, July 22, 2021
Scientific Responsible name : Massimo MANTEGAZZA
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 1 October 2021
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly
Description of the thesis topic
Voltage-gated Na+ channels (Nav) are essential for the generation and propagation of action potentials (APs), and mutations of the Nav1.2 isoform (SCN2A gene) cause neurodevelopmental disorders with a remarkably large clinical spectrum. In particular, numerous Nav1.2 mutations cause severe late infantile-childhood neurodevelopmental disorders (LICND) with onset between 3 months and few years of age: a) developmental and epileptic encephalopathies (DEE) with various degrees of autism spectrum disorder (ASD) and intellectual disability (ID) b) severe ASD without epilepsy, c) severe ID without epilepsy & d) schizophrenia without epilepsy. Notably, recent large-scale human genetic studies have indicated that Nav1.2 mutations are among those that show the strongest association with ASD. It has been proposed that LICND mutations induce reduction of Nav1.2 function, but mechanisms linking reduced function to clinical phenotypes are not completely understood yet. In addition, we have identified a novel pathological mechanism for mutations causing LICND with severe ASD, leading to a larger loss of Nav1.2 function. Importantly, there are no effective treatments for LICND and there are no Nav1.2 enhancers available for increasing its function. We aim to: 1) develop and test drugs and strategies for counteracting reduced Nav1.2 function (targeting also the novel mechanism that we identified), which could be used to treat severe LICND; 2) study pathological mechanisms and effects of treatments in vitro, ex vivo and in vivo.
– Methods. Electrophysiology in transfected cells and brain slices (patch-clamp) and in vivo (video-EEG, LFP), behavioral studies, pharmacological experiments and AAV viral delivery; use a new conditional gene targeted mouse model that we have generated (which carries a Nav1.2 human mutation causing the new pathological mechanism that we have identified); use of the cre-lox system (mouse lines and stereotaxic local brain injections). A novel sodium imaging techniques to optically record sodium currents will be used in collaboration with Marco Canepari (University of Grenoble).
Our group is expert in the study of the pathophysiology of ion channels and neuronal excitability, and all the tools and techniques are available. The group is part of the Institute of Molecular and Cellular Pharmacology (IPMC; www.ipmc.cnrs.fr), which is affiliated to the Université Côte d'Azur (UCA; http://univ-cotedazur.fr) and the French National Center for Scientific Research (CNRS; http://www.cnrs.fr/), and has state of the art shared research facilities; it is located in the technological park of Sophia Antipolis (https://www.sophia-antipolis.fr/en/), in the French Riviera, near Nice.
A pre-selection will be made according to CV, letter of recommendation and results obtained in the Master program.
– Mantegazza M., Cestèle S and Catterall W.A. (2021) Sodium Channelopathies of Skeletal Muscle and Brain. Physiological Reviews. https://doi.org/10.1152/physrev.00025.2020
– Chever O. et al. (2020) GABAergic neurons and NaV1.1 channel hyperactivity: a novel neocortex-specific mechanism of Cortical Spreading Depression. bioRxiv 2020.03.14.991158; Preprint. https://doi.org/10.1101/2020.03.14.991158
– Lena I. and Mantegazza M. (2019) Nav1.2 haploinsufficiency in Scn2a knock-out mice causes an autistic-like phenotype attenuated with age. Scientific Reports 9(1):12886. https://doi.org/10.1038/s41598-019-49392-7
– Salgueiro-Pereira et al. (2019) A two-hit story: seizures and genetic mutation interaction sets phenotype severity in SCN1A epilepsies. Neurobiology of Disease 125:31-44. https://www.ncbi.nlm.nih.gov/pubmed/30659983
– Terragni B. et al. (2018) Post-translational dysfunctions in channelopathies of the nervous system. Neuropharmacology 132:31-42. https://www.ncbi.nlm.nih.gov/pubmed/28571716
– Mantegazza M. et al. (2010) Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders. Lancet Neurology. 9(4):413-424. Review. https://www.ncbi.nlm.nih.gov/pubmed/20298965
Constraints and risks
No constraints. Biological and chemical risks.
Send a CV and the names and contact of two references.
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