Project ID NS-MH2023_46


Co Supervisor 1A IoPPN/Forensic & Neurodevelopmental SciencesWebsite

Co Supervisor 1B IoPPN/Forensic & Neurodevelopmental SciencesWebsite

Building the brain- Making and breaking synapses with cholesterol

The brain is made of billions of neurons which communicate with each other via synapses. Synapse formation (synaptogenesis), function, plasticity, and maintenance – processes crucial for normal brain development and function – are all controlled by cholesterol. Forming up to 25% of the body’s cholesterol, dysregulation of the brain cholesterol metabolism is associated with neurodegenerative (e.g. Alzheimer’s disease) and neurodevelopmental disorders, such as autism. Atypical levels of cholesterol were reported in some autistics (and their parents). Similarly, our group found cholesterol disturbances in several genetic and environmental rodent models of autism that also show synaptic deficits, aberrant brain function and behavioural deficits. However, it is still not known: i) how cholesterol regulates synapses in the healthy brain, ii) how that process is affected in autistic people (and the impact on behaviour), iii) which autism-linked genetic mutations and stress-related experiences result in dysregulated cholesterol metabolism. iv) how this is associated with brain metabolism.

These questions will be addressed in this translational PhD project using mouse models. Through our collaboration with the largest autism consortium, AIMS2-TRIALS, we will address the third and fourth question by testing cholesterol levels in the blood of autistic individuals and linking that to their genotype, environmental factors, and clinical features, as well as by testing cholesterol against neurometabolite levels as acquired using in vivo magnetic resonance spectroscopy. This approach has the potential to develop a new biomarker for patient stratification and pave the way for development of specific and targeted (personalized) treatments.

Overarching objectives:
Year1: in vitro examination of the role of cholesterol in synapse formation and function
Year2: examining the role of autism-related mutations on cholesterol-dependent synapse formation and function
Year3: continuing the Year 2 experiments and testing human blood samples and MRS (autism and controls) for cholesterol and metabolite levels and linking these with patients’ genotypes

Skills training:
Cell culture, electrophysiology, optogenetics, animal behaviour, pharmacological treatments, immunohisto- and neurochemistry, clinical assessments, normative modelling and multivariate approaches (e.g. clustering techniques) for patient stratification

One representative publication from each co-supervisor:

MM Petrinovic, R Hourez, EM Aloy, G Dewarrat, D Gall, O Weinmann, J Gaudias, LC Bachmann, SN Schiffmann, KE Vogt, ME Schwab. “Neuronal Nogo-A negatively regulates dendritic morphology and synaptic transmission in the cerebellum”. PNAS, 2013. doi: 10.1073/pnas.1214255110

He J. L., Oeltzschner G., Mikkelsen M., Deronda A., Harris A. D., Crocetti D., Wodka E. L., Mostofsky S. H., Edden R. A. E. E., Puts N. A. J. (2021). Region-specific elevations of glutamate + glutamine correlate with the sensory symptoms of autism spectrum disorders. Transl Psychiatry 11: 1–35: doi: 10.1038/s41398-021-01525-1.