Gene–Environment Interactions in Neurodevelopmental Disorders: GABAergic Dysregulation and Sleep Circuit Dysfunction

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: Dysregulated GABA signalling during critical developmental windows can reshape excitation/inhibition (E/I) balance, mechanisms now recognised as central to autism spectrum disorder (ASD) pathophysiology. Sleep disturbances affect a large proportion of autistic individuals and correlate with more severe core symptoms and reduced quality of life. GABAergic circuits regulate sleep–wake transitions and NREM/REM organisation, and altered GABA receptor function and E/I imbalance are implicated in atypical sleep architecture in ASD. Pyrethroid insecticides such as deltamethrin (DTM) are widely used and frequently detected in air and human biomonitoring samples, including during pregnancy. Beyond their classical action on voltage-gated sodium channels, pyrethroids directly interact with chloride channels and GABA receptors, raising concern about interference with developmental GABA signalling.  MAGEL2-associated syndromes (Prader–Willi and Schaaf–Yang) are neurodevelopmental disorders characterised by ASD features, cognitive impairment and sleep abnormalities. Magel2 knockout (KO) mice reproduce several of these phenotypes, with marked inter-individual variability suggesting strong gene–environment interactions. 

Scientific Objective : To determine how early-life airborne DTM exposure interacts with Magel2 deficiency to disrupt hippocampal GABA development, E/I balance, synaptic plasticity, and sleep–wake organisation, and how these alterations relate to ASD-like phenotypes.

Specific Objectives and methods: The PhD candidate will combine ex vivo hippocampal electrophysiology with in vivo EEG/EMG sleep analysis. 1-Hippocampal E/I balance (juvenile stage) : Quantify spontaneous glutamatergic and GABAergic synaptic activity in CA1 pyramidal neurons from WT and Magel2 KO mice ± DTM exposure. 2-Developmental GABA polarity switch : Determine the timing of the depolarising-to-hyperpolarising GABA shift across key postnatal stages in WT and Magel2 KO offspring ± DTM. 3-Sleep–wake architecture and network activity : Characterise EEG/EMGdefined vigilance states and sleep microstructure in WT and Magel2 KO mice ± DTM, and relate sleep signatures to hippocampal physiology and ASDlike behaviours.

Expected results: We expect that early-life airborne exposure to the GABA-targeting pyrethroid deltamethrin acts as an environmental “second hit” that interacts with Magel2 deficiency to exacerbate ASD-relevant circuit dysfunction and sleep disturbances. We hypothesise that gestational and early postnatal DTM exposure in Magel2 KO mice delays or disrupts the developmental GABA polarity switch, shifts hippocampal E/I balance, impairs long-term potentiation (LTP), and alters sleep–wake organisation, thereby worsening behavioural and sleep phenotypes relative to either factor alone.

Feasibility:  Magel2 KO mice, exposure protocols are fully established in the host laboratory. Ethical approvals is already obtained for WT mice.

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 : experience in Electrophysiology, background in data analyses and computational neurosciences