Pleiotropic effects of schizophrenia-associated genetic variants in neuron firing and cardiac pacemaking revealed by computational modeling

Figures

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  Fig. 1. Effects of Na+ and HCN channel gene variants on L5PC and SANC excitability are qualitatively similar a The membrane-potential time courses of the modeled cells in control cells and Na+ channel variant cells. The L5PCs are stimulated with a somatic DC of amplitude 1.0 nA (Hay model, top panel) or 0.8 nA (Almog model, second from top) to induce stable spiking, while the SANCs rhythmically fire cardiac action potentials without any external stimulus (Kharche model third from top, Severi model on the bottom panel). Different colors represent different scalings of the same variant, parametrized by variable \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\epsilon$$\end{document}ϵ. Variants with \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\epsilon {\mathbf{ = }}\frac{1}{2}$$\end{document}ϵ=12 and \documentclass[12pt]{minimal}…

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  Fig. 2. Ca2+ channel gene variants typically have opposite effects on L5PC firing and SANC pacemaking a The membrane potential time courses in control cells and cells implemented with a CACNA1C variant (the first variant in Supplementary Table S2), see Fig. 1a. b The f–I curves and pacemaking rhythms of the modeled cells implemented with a Ca2+ channel or transporter variant, see Fig. 1b. Apart from the CACNA1I variants that show mixed effects, it can be seen that those variants that increase the pacemaking rhythm in SANCs, decrease the L5PC firing frequency, and vice versa. Variant effects on threshold currents in L5PCs are generally small

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  Fig. 3. Overview of variant effects on L5PC firing and SANC pacemaking The average firing frequencies and pacemaking rhythms are shown for all variants of Supplementary Table S2. Top panel: Firing rates in the Hay model, averaged over stimulus amplitudes 0.35–1.4 nA. Second panel: Firing rates in the Almog model, averaged over stimulus amplitudes 0.7–0.9 nA. Third panel: Pacemaking rates in the Kharche model. Bottom panel: Pacemaking rates in the Severi model. See Figs. 1 and 2 for more detailed data. Variants shown in Figs. 1 and 2 are highlighted with asterisks, and variants used in combinations of Supplementary Fig. S10 are highlighted with crosses (' × ') and circles (' ∘ ')

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  Fig. 4. Signal propagation from SAN to surrounding atria is altered in a Ca2+ channel variant A tissue of size 3 × 3 cm was modeled using a diffusion constant of 1.2 cm2/s in the direction of the monitored fiber and 0.25 cm2/s in the direction orthogonal to this. A spatial resolution of 151 × 151 nodes (0.02 cm) and temporal resolution of ∆t = 0.125 ms was used. The panels show the membrane potential as a function of time at six different locations of the modeled tissue for different scalings of a CACNA1C variant (the first variant of Supplementary Table S2). The center (blue) expresses membrane potential dynamics similar to that seen in single-cell experiments (Figs. 1 and 2), while near the borders (magenta and yellow), the action potentials are sharper and more alike to those presented in ref.62. The left panels (A) show the results in a model tissue with a smaller (radius 0.27 cm) SAN, and the right panels (B) show the results using a larger (radius 0.40 cm) SAN. In the variants with smallest effect (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek}…