CACNA1C TS-II variants alter single-cell dynamics in computational models of cortical pyramidal cells

Timothy Syndrome (TS) is a rare multi-system disorder and a monogenic calcium channelopathy. Previous computational work on this disorder has focused on the myocardium, ignoring the effects of TS on neural development and its strong association with autism spectrum disorder. Variation in the TS-causative gene, CACNA1C , is indeed also associated with a variety of complex neurodevelopmental and neuropsychiatric disorders. We apply computational methods, drawing on experimental data, to understand the mechanisms of calcium dysregulation in TS, and validate our findings in four well-established multi-compartmental neuronal models. CACNA1C encodes the L-type voltage-gated calcium channel, Ca _v 1.2, which modulates neuronal excitability and several activity-dependent pathways. We investigate two mutations in CACNA1C causative of TS type II, Ca _v 1.2 ^G406R and Ca _v 1.2 ^G402S . Both variants show a loss of voltage-dependent inactivation and changes in their voltage dependence of activation. We incorporate the altered steady-state activity of these variants with additional morphological data indicating a significant increase in activity-dependent dendritic retraction of layer II/III pyramidal cells in TS mutant neurones. Our findings replicate experimental work suggesting that increased Ca ²⁺ flux reduces firing frequency but does not affect the rheobase current for action potential initiation. Furthermore, models expressing dendritic Ca _v 1.2 current show altered apical-somatic signal integration in mutant neurones. All models with shortened dendrite morphology show hyperexcitability, denoted by reduced rheobase current and increased responsiveness to current injection compared to their full-length counterparts. Importantly, our approach identifies robust and testable predictions on the impacts of TS on single-cell dynamics. We also discuss the broader implications of our findings for other Ca ²⁺ -related neurodevelopmental and neuropsychiatric disorders.