Project ID NS-MH2023_04

ThemeNS-MH

Co Supervisor 1A Faculty of Dentistry/Centre for Craniofacial & Regenerative Biology and MRC Centre for Neurodevelopmental DisordersWebsite

Co Supervisor 1B IoPPN/Centre for Developmental NeurobiologyWebsite

Epigenetic and circuit abnormalities in neurodevelopmental disorders

Mutations in epigenetic regulators have emerged as a significant risk factor for a diverse group of neurodevelopmental disorders, with most characterised by autism and intellectual disability. We have generated mouse models with mutations in these high risk genes that encode epigenetic regulators. The over-arching aim of this project is to identify the molecular, epigenetic, cellular and circuit abnormalities that underlie these conditions, and their associated behavioural phenotypes, with the ultimate objective of eventually being able to use this information to develop new treatments.

Techniques and skills include conditional, targeted gene deletion, behavioural assays, patch clamp electrophysiology, optogenetics, next generation sequencing and a range of molecular approaches including qRT-PCR, ChIP, Western blot, immunostaining, immunoprecipitation and advanced imaging / microscopy techniques, tailored to suit student preferences and priorities.

Year 1: To use patch clamp electrophysiology and synaptic imaging to comprehensively characterise synaptic and plasticity abnormalities in the prefrontal cortex.

Year 2: To use a combination of cell type specific conditional gene deletion, patch clamp electrophysiology and optogenetics to comprehensively characterise cell-type-specific synaptic phenotypes.

Year 3-4: To use next generation sequencing, molecular and imaging techniques and behavioural assays to identify cell type specific mechanisms that underpin specific behavioural abnormalities.

Together, this project will link epigenetic perturbations in specific neuronal cell types to circuit and synaptic abnormalities responsible for behavioural and cognitive phenotypes associated with specific neurodevelopmental conditions.

Representative Publications

Hurley, S., Mohan, C., Suetterlin, P., Ellingford, R., Riegman, K.L.H., Ellegood, J., Caruso, A. , Michetti, C., Brock, O., Evans, R., Rudari, F., Delogu, A., Scattoni, M.L., Lerch, J.P., Fernandes, C. & Basson, M.A. (2021) Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development. Mol. Autism 12:16.

Ellingford, R.A., Panasiuk, M.J., Rabeshala De Meritens, E., Shaunak, R., Naybour, L., Browne, L., Basson, M.A.*, Andreae, L.C.* (2021) Cell-type-specific synaptic imbalance and disrupted homeostatic plasticity in cortical circuits of ASD-associated Chd8 haploinsufficient mice. Mol. Psych. doi: 10.1038/s41380-021-01070-9 *Joint corresponding authors https://doi.org/10.1101/2020.05.14.093187