Investigating the molecular bases of pathogenic excitability changes in cortical malformations

The NeuroSchool PhD Program of Aix-Marseille University (France) has launched its annual calls for PhD contracts for students with a master's degree in a non-French university. 

This project is one of the proposed projects. Not all proposed projects will be funded, check our website for details.

State of the art: Cortical malformations are a major cause of drugresistant epilepsy in children and adolescents. Studying the pathophysiological mechanisms that lead to these epilepsies is challenging because malformations are typically diagnosed only after the first seizure. In addition, it is impossible to directly access to the pathological changes that occur in the brains of patients and contribute to epilepsy. In this context, clinically relevant rodent models could improve our understanding of the disease onset and progression, ultimately leading to better therapies. 

Objectives: To investigate the underlying bases of altered neuronal excitability in rodent models with grey matter heterotopia, a group of cortical malformations associated with epilepsy. The project will address whether and how a series of candidate genes which have been identified using existing transcriptomic datasets could contribute to epilepsy by altering excitability. Additional single-cell transcriptomic datasets will also be generated, analyzed, and exploited during the project. 

Methods: Will combine transcriptomics and molecular biology; in vivo stereotactic injection of viral vectors and postnatal electroporation to express/repress candidate genes; histology and microscopy; in vivo seizure susceptibility tests. 

Expected results: Clarification of the underlying pathological mechanisms contributing to altered excitability and seizures in grey matter heterotopia models. Proof-of-concept for therapy-oriented approaches (some will be tested) aimed at reversing altered excitability, first in rodent models and ultimately in patients

Feasibility:  3 murine models with cortical malformations; in-house molecular and cellular biology platform and imaging facility; project authorization for animal research (APAFIS#26835-2020080610441911 v2, to be renewed); ongoing local and international collaborations, including with human epileptologists and geneticists.

Within Aix Marseille Université, NeuroMarseille brings together 8 research laboratories and NeuroSchool, a graduate school in neuroscience, to increase the attractiveness of the university, international collaborations, interdisciplinarity, links with the clinical and industrial worlds and the integration of students into professional life. 

Launched in July 2018, NeuroSchool unifies and harmonizes the training of the third year of the Bachelor of Life Sciences (Neuroscience track), the Master's and the PhD in Neuroscience. 

• Expected candidate profile : Prior experience with bioinformatics and transcriptomics; Prior experience with rodent handling and surgeries; Histology and microscopy; Molecular biology.