Abstract
Mutations in the calcium channel (Cav1.2) gene, CACNA1C, are well-associated with various heritable brain disorders, yet their effects on neuronal function are not definitively understood. We employ computational models to investigate Timothy Syndrome (TS) - a multi-system disorder clearly defined by electrophysiologically characterized gain-of-function mutations in CACNA1C. In doing so, we aim to generate generalizable insights on the effects of altered calcium dynamics in CACNA1C-associated brain disorders. We investigated the effects of two CACNA1C variants causative of TS type II, Cav1.2G406R and Cav1.2G402S, incorporating known steady-state activation and inactivation properties of mutant channels along with morphological changes found in TS. These parameters were implemented in four well-established multi-compartmental neuronal models. Notably, our approach was able to distinguish between two potential mechanisms of altered signalling dynamics, namely the consequences of dendritic shortening, which is an indirect developmental result of the mutations, and heightened calcium flux through mutant channels, which is a direct effect of the altered channel activation properties. Our models replicated experimental observations showing a reduction in firing frequency without affecting action potential threshold. Furthermore, models predicted hyperexcitability in instances of shortened dendrite morphology and additive effects of the two mechanisms on apical-somatic signal integration. Our findings offer robust, testable predictions on the impacts of TS on single-cell dynamics, enhancing our understanding of similar CACNA1C-associated pathologies.
Original language | English |
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Pages | 5151 |
Publication status | Published - 2024 |
Publication type | Not Eligible |
Event | Annual Computational Neuroscience Meeting - Leipzig, Germany Duration: 15 Jul 2023 → 19 Jul 2023 |
Conference
Conference | Annual Computational Neuroscience Meeting |
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Country/Territory | Germany |
City | Leipzig |
Period | 15/07/23 → 19/07/23 |