NCMD Seminar Presents 'Studying and rescuing the functional phenotypes of psychotic and autistic models using iPSD-derived patient neurons'

Neural network

During this weeks NCMD Seminar, we were pleased to welcome Dr Mouhamed Alsaqati, lecturer in neuropharmacology at Newcastle University. Dr Alsaqati's research is predominantly in the fields of neuropsychiatry, neurodegeneration, stem cell neurology and pain. For this weeks talk, he delivered a fantastic presentation called 'Studying and rescuing functional phenotypes of psychotic and autistic models using iPSD-derived patient neurons'.

Investigating the biology of rare but relatively high penetrant genetic variants, provides an opportunity to understand the genetic basis of an increased susceptibility to a range of neurological disorders. Here they apply multi-electrode array-based assays to study the effects of TSC2 mutation on neuronal network activity autistic patient’s iPSC-derived neurons; carrying TSC mutation. 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.

They 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.

Their 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 could 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.

Thank you very much to Dr Alsaquati!

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