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Tuesday 21 Jun 2022Emerging hiPSC-derived neuronal models for studying the functional phenotype of neurodevelopmental disorders

Mouhamed Alsaqati - University of Cardiff

LSI Seminar Room A 13:30-14:30

The combination of the multi-electrode arrays (MEAs) technology and the neuronal differentiation of stem cells provides a platform to study the network behaviour of patient or engineered human cellular models. We apply multi-electrode array-based assays to study the effects of TSC2 mutation on neuronal network activity using autism spectrum disorder (ASD) patient-derived iPSCs. Tuberous sclerosis complex (TSC) is a rare genetic disorder resulting from autosomal dominant mutations in the TSC1 or TSC2 genes. It is characterised by hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and has severe neurodevelopmental and neurological components including autism, intellectual disability and epilepsy. In human and rodent models, loss of the TSC proteins causes neuronal hyperexcitability and synaptic dysfunction, although the consequences of these changes for the developing central nervous system are currently unclear. We find that ASD patient-derived neurons with a functional loss of TSC2 develop a dysfunctional neuronal network with reduced synchronisation of neuronal bursting and lower spatial connectivity. These deficits are associated with excitatory/inhibitory imbalance. The mTOR inhibitor rapamycin suppresses neuronal hyperactivity, but does not increase synchronised network activity, whereas activation of ULK1 signalling by LYN-1604 increases the network behaviour, shortens the network burst lengths and reduces the number of uncorrelated spikes. Our observations suggest that there is a reduction in the network connectivity of the in vitro neuronal network associated with ASD patients with TSC2 mutation, which may arise via an excitatory/inhibitory imbalance due to increased GABA-signalling at inhibitory synapses. This may underlie TSC symptoms such as autistic features. This abnormality can be effectively suppressed via activation of ULK1. Understanding the excitatory/inhibitory neuronal populations and how they interact in the culture may be used to rescue the abnormal phenotype of various neurodevelopmental models.  

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