The neurophysiology of a mouse model of Timothy Syndrome

Craddock, Rosie 2024. The neurophysiology of a mouse model of Timothy Syndrome. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Timothy syndrome (TS) is a multisystemic genetic disorder involving neuropsychiatric symptoms. TS is caused by heterozygous functional mutations in the neurophysiologically relevant calcium voltage-gated channel subunit α1c (CACNA1C) gene. Notable symptoms of TS are cardiac arrhythmia (long QT), syndactyly, hypoglycaemia, facial dysmorphisms, and neuropsychiatric phenotypes including autism spectrum disorder, epilepsy, and neurodevelopmental delay. Three well characterised mutations in the CACNA1C gene, defined here as classical TS mutations, encode CaV1.2 channel α-1 subunits which lack voltage-dependent inactivation. On cell depolarisation, these channels allow a prolonged calcium influx into the cell. In cardiomyocytes this causes a prolonged action potential (AP), leading to long QT. TS mutations also impact cell development and migration around the body. It is unknown how classical TS mutations impact neuronal function. In this thesis I investigate some of the neurophysiological changes resulting from the classical TS2 mutation. I explored how the TS2 mutation impacts basic visual processing, neuronal electrophysiology and parvalbumin inhibitory interneuron distribution across the brain using the TS2Neo mouse model of TS. I predict how the mutation will influence neural networks oscillations by use of computational modelling. Functional imaging demonstrated that TS2 alters a specific aspect of basic visual processing in mouse visual cortical cells, increasing contrast sensitivity to high spatial frequency visual stimuli. I provide the first electrophysiological evidence that classical TS mutations prolong the AP of mature pyramidal neurons within naturally developed, acute mouse brain tissue in the primary visual cortex, retrosplenial cortex and in CA1 of the hippocampus. I use immunofluorescent imaging to show that TS2 alters parvalbumin interneuron distribution across the mouse brain, with an increase in density in the visual cortex, and a decrease in density in the CA3 of the hippocampus. Computational modelling predicted that the mutation-related reduction in parvalbumin interneuron number reduces ɣ oscillatory power in the CA3.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	15 August 2024
Last Modified:	15 Aug 2024 15:52
URI:	https://orca.cardiff.ac.uk/id/eprint/171419

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