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Genetically engineered MAPT 10+16 mutation causes pathophysiological excitability of human iPSC-derived neurons related to 4R tau-induced dementia

Kopach, Olga, Esteras, Noemí, Wray, Selina, Abramov, Andrey Y., Rusakov, Dmitri A.·2021·Cell Death & Disease
DOI 10.1038/s41419-021-04007-wPMC PMC8286258
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Abstract

Human iPSC lines represent a powerful translational model of tauopathies. We have recently described a pathophysiological phenotype of neuronal excitability of human cells derived from the patients with familial frontotemporal dementia and parkinsonism (FTDP-17) caused by the MAPT 10+16 splice-site mutation. This mutation leads to the increased splicing of 4R tau isoforms. However, the role of different isoforms of tau protein in initiating neuronal dementia-related dysfunction, and the causality between the MAPT 10+16 mutation and altered neuronal activity have remained unclear. Here, we employed genetically engineered cells, in which the IVS10+16 mutation was introduced into healthy donor iPSCs to increase the expression of 4R tau isoform in exon 10, aiming to explore key physiological traits of iPSC-derived MAPT IVS10+16 neurons using patch-clamp electrophysiology and multiphoton fluorescent imaging techniques. We found that during late in vitro neurogenesis (from ~180 to 230 days) iPSC-derived cortical neurons of the control group (parental wild-type tau) exhibited membrane properties compatible with “mature” neurons. In contrast,MAPT IVS10+16 neurons displayed impaired excitability, as reflected by a depolarized resting membrane potential, an increased input resistance, and reduced voltage-gated Na+- and K+-channel-mediated currents. The mutation changed the channel properties of fast-inactivating Na v and decreased the Na v 1.6 protein level.MAPT IVS10+16 neurons exhibited reduced firing accompanied by a changed action potential waveform and severely disturbed intracellular Ca 2+dynamics, both in the soma and dendrites, upon neuronal depolarization. These results unveil a causal link between the MAPT 10+16 mutation, hence overproduction of 4R tau, and a dysfunction of human cells, identifying a biophysical basis of changed neuronal activity in 4R tau-triggered dementia. Our study lends further support to using iPSC lines as a suitable platform for modelling tau-induced human neuropathology in vitro.

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Figures

Fig. 1 Electrophysiological properties of human iPSC-derived neurons with wild-type tau background even out at late neurogenesis. A Left, DIC image of human iPSC-derived neuronal culture at ~190 DIV showing a patched neuron. Right, statistics of the resting membrane potential (Vrest) of iPSC-derived neurons in control (wild type, wt, tau) line at ~190 and 220 DIV. The two-tailed unpaired t-test indicated. B Statistics of the capacitance (Cm) of iPSC-derived neurons in the control (wt tau) group at different time points. Boxes show median values. Nonparametric Mann–Whitney test indicated. C Left, example of neuron responses (current mode) to a series of hyperpolarizing currents (top); lower panel shows how the membrane constant (τm) was measured. Dotted box, the area for calculating τm (red, linear fit). Right, statistics of the τm value in wt tau neurons at different time points. The two-tailed unpaired t-test indicated. D Same as in (B), but for the input resistance (Rin). The two-tailed unpaired t-test indicated. E Representative recording of changes in membrane potential of an iPSC-derived neuron in response to a hyperpolarizing current (indicated on the top) for the calculation of the voltage drop (Vdrop) and the sag ratio. F Statistical summary for the Vdrop (left) and the sag ratio (right) of control (wt tau) neurons at different time points. The two-tailed unpaired t-test indicated. All data are mean with s.e.m, unless indicated. The number of tested cells shown.
Fig. 1 Electrophysiological properties of human iPSC-derived neurons with wild-type tau background even out at late neurogenesis. A Left, DIC image of human iPSC-derived neuronal culture at ~190 DIV showing a patched neuron. Right, statistics of the resting membrane potential (Vrest) of iPSC-derived neurons in control (wild type, wt, tau) line at ~190 and 220 DIV. The two-tailed unpaired t-test indicated. B Statistics of the capacitance (Cm) of iPSC-derived neurons in the control (wt tau) group at different time points. Boxes show median values. Nonparametric Mann–Whitney test indicated. C Left, example of neuron responses (current mode) to a series of hyperpolarizing currents (top); lower panel shows how the membrane constant (τm) was measured. Dotted box, the area for calculating τm (red, linear fit). Right, statistics of the τm value in wt tau neurons at different time points. The two-tailed unpaired t-test indicated. D Same as in (B), but for the input resistance (Rin). The two-tailed unpaired t-test indicated. E Representative recording of changes in membrane potential of an iPSC-derived neuron in response to a hyperpolarizing current (indicated on the top) for the calculation of the voltage drop (Vdrop) and the sag ratio. F Statistical summary for the Vdrop (left) and the sag ratio (right) of control (wt tau) neurons at different time points. The two-tailed unpaired t-test indicated. All data are mean with s.e.m, unless indicated. The number of tested cells shown.CC BY · PubMed Central
Fig. 2 MAPT IVS10+16 neurons display a depolarized resting membrane potential and increased resistance, but unchanged other parameters of interest. A Immunofluorescence staining of human iPSC-derived cells for β-tubulin III (red), GFAP (green), and nuclear marker Hoechst 33342 (blue) at 130 DIV in a control cell culture (wt tau, left) and a genetically engineered one (right image). Right, quantification of the relative area of GFAP versus β-tubulin III shows a similar proportion of astroglia between the isogenic control and MAPT IVS10+16 groups (total n = 6 cell cultures per group, p = 0.702; the two-tailed unpaired t-test). B Statistics of the resting membrane potential (Vrest) of iPSC-derived neurons in control (wt tau) and MAPT IVS10+16 groups during late neurogenesis (~190–220 DIV). ***P < 0.001 (two-tailed unpaired t-test). C Statistics of the capacitance (Cm) of iPSC-derived neurons in control (wt tau) and MAPT IVS10+16 groups. Boxes show median values. Nonparametric Mann–Whitney test indicated. D Same as in (B), but for the input resistance (Rin). The two-tailed unpaired t-test indicated. E Same as in (C), but for the membrane constant (τm). Boxes show median values. Nonparametric Mann–Whitney test indicated. F Left, an overlay of the membrane potential changes in response to a hyperpolarizing current (on the top) in a control (wt tau) neuron (black line) and a MAPT IVS10+16 neuron (red line). Right plots, statistics of the Vdrop and the sag ratio of (right) in the wt tau and MAPT IVS10+16 groups. The two-tailed unpaired t-test indicated. All data are mean with s.e.m, unless indicated. The number of tested cells indicated.
Fig. 2 MAPT IVS10+16 neurons display a depolarized resting membrane potential and increased resistance, but unchanged other parameters of interest. A Immunofluorescence staining of human iPSC-derived cells for β-tubulin III (red), GFAP (green), and nuclear marker Hoechst 33342 (blue) at 130 DIV in a control cell culture (wt tau, left) and a genetically engineered one (right image). Right, quantification of the relative area of GFAP versus β-tubulin III shows a similar proportion of astroglia between the isogenic control and MAPT IVS10+16 groups (total n = 6 cell cultures per group, p = 0.702; the two-tailed unpaired t-test). B Statistics of the resting membrane potential (Vrest) of iPSC-derived neurons in control (wt tau) and MAPT IVS10+16 groups during late neurogenesis (~190–220 DIV). ***P < 0.001 (two-tailed unpaired t-test). C Statistics of the capacitance (Cm) of iPSC-derived neurons in control (wt tau) and MAPT IVS10+16 groups. Boxes show median values. Nonparametric Mann–Whitney test indicated. D Same as in (B), but for the input resistance (Rin). The two-tailed unpaired t-test indicated. E Same as in (C), but for the membrane constant (τm). Boxes show median values. Nonparametric Mann–Whitney test indicated. F Left, an overlay of the membrane potential changes in response to a hyperpolarizing current (on the top) in a control (wt tau) neuron (black line) and a MAPT IVS10+16 neuron (red line). Right plots, statistics of the Vdrop and the sag ratio of (right) in the wt tau and MAPT IVS10+16 groups. The two-tailed unpaired t-test indicated. All data are mean with s.e.m, unless indicated. The number of tested cells indicated.CC BY · PubMed Central
Fig. 3 Pathogenic 4R tau decreases both voltage-gated Na+- and K+-currents, changes Na+-channel property, and reduces Nav1.6 protein level. A Representative patch-clamp recordings showing inward and outward currents recorded from a control (wild type, wt, tau) iPSC-derived neuron (left) and a MAPT IVS10+16 neuron (right). The protocol consisted of voltage steps from −100 mV to +80 mV, increment of 5 mV (indicated on the bottom). Red line, the current recorded at –10 mV; box depicts the fast-activating and -inactivating current shown on an expanded scale. B Left, statistics for the peak Na+-current (INa) in isogenic control (wt tau) and MAPT IVS10+16 neurons. Boxes show median values; *p < 0.05 (nonparametric Mann–Whitney test). Right, current–voltage (I–V) relationship for the INa recorded from both groups of neurons. Protocol as in (A). C Example of persistent inward current recordings from a MAPT IVS10+16 neuron (voltage steps from −50 mV to −20 mV, increment of 5 mV). Red line, the current recorded at –30 mV; arrow and dashed lines depict persistent currents (Ipersistent). Statistics of the relative persistent current normalized to peak current for each individual cell in wt tau (n = 8 cells) and MAPT IVS10+16 groups (n = 12 neurons) at membrane potentials tested. D Conductance–voltage relationships of INa in wt tau and MAPT IVS10+16 neurons. Conductance was normalized to the maximal INa conductance; lines are Boltzmann fitting. E A representative western blot for the Nav1.6 channel isoform in iPSC-derived neurons at ~200 DIV in wt tau and MAPT IVS10+16 cultures with β-tubulin III as loading control (left), and statistics for the protein expression level of Nav1.6 channel in both groups (n = 3 samples per group). *P = 0.018 (the two-tailed unpaired t-test). All data are mean with s.e.m, unless indicated. The number of tested cells indicated.
Fig. 3 Pathogenic 4R tau decreases both voltage-gated Na+- and K+-currents, changes Na+-channel property, and reduces Nav1.6 protein level. A Representative patch-clamp recordings showing inward and outward currents recorded from a control (wild type, wt, tau) iPSC-derived neuron (left) and a MAPT IVS10+16 neuron (right). The protocol consisted of voltage steps from −100 mV to +80 mV, increment of 5 mV (indicated on the bottom). Red line, the current recorded at –10 mV; box depicts the fast-activating and -inactivating current shown on an expanded scale. B Left, statistics for the peak Na+-current (INa) in isogenic control (wt tau) and MAPT IVS10+16 neurons. Boxes show median values; *p < 0.05 (nonparametric Mann–Whitney test). Right, current–voltage (I–V) relationship for the INa recorded from both groups of neurons. Protocol as in (A). C Example of persistent inward current recordings from a MAPT IVS10+16 neuron (voltage steps from −50 mV to −20 mV, increment of 5 mV). Red line, the current recorded at –30 mV; arrow and dashed lines depict persistent currents (Ipersistent). Statistics of the relative persistent current normalized to peak current for each individual cell in wt tau (n = 8 cells) and MAPT IVS10+16 groups (n = 12 neurons) at membrane potentials tested. D Conductance–voltage relationships of INa in wt tau and MAPT IVS10+16 neurons. Conductance was normalized to the maximal INa conductance; lines are Boltzmann fitting. E A representative western blot for the Nav1.6 channel isoform in iPSC-derived neurons at ~200 DIV in wt tau and MAPT IVS10+16 cultures with β-tubulin III as loading control (left), and statistics for the protein expression level of Nav1.6 channel in both groups (n = 3 samples per group). *P = 0.018 (the two-tailed unpaired t-test). All data are mean with s.e.m, unless indicated. The number of tested cells indicated.CC BY · PubMed Central
Fig. 4 Overexpression of 4R tau decreases the voltage-gated K+-current density but not conductance. A Statistics for the amplitude of K+-current (IK) measured at 30 mV (upper bars) and 80 mV (lower bars) in isogenic control (wt tau) and MAPT IVS10+16 neurons. Boxes show median values; ***p < 0.001 (nonparametric Mann–Whitney test). The number of tested cells indicated. B. I–V relationship for the IK density in the isogenic control (wt tau) and the MAPT IVS10+16 cohorts. C. Conductance–voltage relationships of IK recorded in wt tau and MAPT IVS10+16 neurons. Conductance was normalized to the maximal IK conductance; lines are Boltzmann fitting.
Fig. 4 Overexpression of 4R tau decreases the voltage-gated K+-current density but not conductance. A Statistics for the amplitude of K+-current (IK) measured at 30 mV (upper bars) and 80 mV (lower bars) in isogenic control (wt tau) and MAPT IVS10+16 neurons. Boxes show median values; ***p < 0.001 (nonparametric Mann–Whitney test). The number of tested cells indicated. B. I–V relationship for the IK density in the isogenic control (wt tau) and the MAPT IVS10+16 cohorts. C. Conductance–voltage relationships of IK recorded in wt tau and MAPT IVS10+16 neurons. Conductance was normalized to the maximal IK conductance; lines are Boltzmann fitting.CC BY · PubMed Central
Fig. 5 MAPT IVS10+16 neurons display impaired action potentials. A Example recordings of action potentials (AP) in a control (wild type, wt, tau) iPSC-derived neuron (left) and a MAPT IVS10+16 neuron (right) elicited by square depolarizing current pulses (indicated on the bottom). B–D Statistics for the AP amplitude (B), the threshold (C) and the width measured at half-maximal amplitude in control (wt tau) and MAPT IVS10+16 neurons. Analysis performed for the first AP spike. Data are mean ± s.e.m. ***P < 0.001, p = 0.031 for (C), and p = 0.039 for (D) (the two-tailed unpaired t-test). Number of cells, n = 9 per group.
Fig. 5 MAPT IVS10+16 neurons display impaired action potentials. A Example recordings of action potentials (AP) in a control (wild type, wt, tau) iPSC-derived neuron (left) and a MAPT IVS10+16 neuron (right) elicited by square depolarizing current pulses (indicated on the bottom). B–D Statistics for the AP amplitude (B), the threshold (C) and the width measured at half-maximal amplitude in control (wt tau) and MAPT IVS10+16 neurons. Analysis performed for the first AP spike. Data are mean ± s.e.m. ***P < 0.001, p = 0.031 for (C), and p = 0.039 for (D) (the two-tailed unpaired t-test). Number of cells, n = 9 per group.CC BY · PubMed Central
Fig. 6 4R tau impairs the intracellular Ca2+ mobilization across neuronal compartments upon depolarization. A Monitoring of depolarization-induced intracellular Ca2+ dynamics using two-photon excitation time-lapse imaging in control (wild type, wt, tau) iPSC-derived neurons (~210 DIV). Images, experimental arrangement for focal application of a high-potassium medium (50 mM) through a micropipette positioned in close proximity of the cells before (left panel) and during a puff of K+ (right panel). Images, combined transmitted light, OGB-1 (green), and Alexa Fluor-594 (red) channels (upper row) and OGB-1 only (lower row); λ2Pex = 800 nm; dotted areas, regions of interest (ROI): cells 1–2 and two neurites, d1 and d2. Plots, the time course of the intracellular Ca2+ rise (ΔF/F0 OGB-1 signal) within indicated ROIs before and following cell depolarization; top trace, Alexa Fluor-594 diffusion profile across the field of view; red arrow, timestamp of K+ puff. B Notations as in (A) but for the MAPT IVS10+16 group. Note the slow and diminished depolarization-induced Ca2+-rise (ΔF/F0 OGB-1 signal), with prolonged decay kinetics, in soma and neurites. C Quantification of the peak Ca2+-rise (ΔF/F0 OGB-1 signal) in response to the two consecutive applications of K+ medium in individual neurons from control (wt tau, n = 17 cells, left bars) and MAPT IVS10+16 groups (n = 34, right). Boxes show median values. The nonparametric paired-sample Wilcoxon signed rank test indicated. D Statistics for the depolarization-induced Ca2+-rise (ΔF/F0 OGB-1 signal) for pooled groups of wt tau and MAPT IVS10+16 neurons recorded in soma (bars show median values, n = 89 cells and 88 cells, respectively, three independent preparations) and within neuronal processes (mean ± SEM, n = 10 per group). ***p < 0.001 nonparametric Mann–Whitney test; ###p < 0.001 ANOVA test.
Fig. 6 4R tau impairs the intracellular Ca2+ mobilization across neuronal compartments upon depolarization. A Monitoring of depolarization-induced intracellular Ca2+ dynamics using two-photon excitation time-lapse imaging in control (wild type, wt, tau) iPSC-derived neurons (~210 DIV). Images, experimental arrangement for focal application of a high-potassium medium (50 mM) through a micropipette positioned in close proximity of the cells before (left panel) and during a puff of K+ (right panel). Images, combined transmitted light, OGB-1 (green), and Alexa Fluor-594 (red) channels (upper row) and OGB-1 only (lower row); λ2Pex = 800 nm; dotted areas, regions of interest (ROI): cells 1–2 and two neurites, d1 and d2. Plots, the time course of the intracellular Ca2+ rise (ΔF/F0 OGB-1 signal) within indicated ROIs before and following cell depolarization; top trace, Alexa Fluor-594 diffusion profile across the field of view; red arrow, timestamp of K+ puff. B Notations as in (A) but for the MAPT IVS10+16 group. Note the slow and diminished depolarization-induced Ca2+-rise (ΔF/F0 OGB-1 signal), with prolonged decay kinetics, in soma and neurites. C Quantification of the peak Ca2+-rise (ΔF/F0 OGB-1 signal) in response to the two consecutive applications of K+ medium in individual neurons from control (wt tau, n = 17 cells, left bars) and MAPT IVS10+16 groups (n = 34, right). Boxes show median values. The nonparametric paired-sample Wilcoxon signed rank test indicated. D Statistics for the depolarization-induced Ca2+-rise (ΔF/F0 OGB-1 signal) for pooled groups of wt tau and MAPT IVS10+16 neurons recorded in soma (bars show median values, n = 89 cells and 88 cells, respectively, three independent preparations) and within neuronal processes (mean ± SEM, n = 10 per group). ***p < 0.001 nonparametric Mann–Whitney test; ###p < 0.001 ANOVA test.CC BY · PubMed Central

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Research works printed but not linked: 54

  1. Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron. 1989;3:519–26. · DOI · Paper page
  2. Matsuo ES, Shin RW, Billingsley ML, Van deVoorde A, O’Connor M, Trojanowski JQ, et al. Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer’s disease paired helical filament tau. Neuron. 1994;13:989–1002. · DOI
  3. Ishizawa T, Mattila P, Davies P, Wang D, Dickson DW. Colocalization of tau and alpha-synuclein epitopes in Lewy bodies. J Neuropathol Exp Neurol. 2003;62:389–97. · DOI
  4. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, et al. Association of missense and 5’-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998;393:702–5. · DOI · Paper page
  5. Pickering-Brown SM, Richardson AM, Snowden JS, McDonagh AM, Burns A, Braude W, et al. Inherited frontotemporal dementia in nine British families associated with intronic mutations in the tau gene. Brain: J Neurol. 2002;125:732–51. · DOI
  6. Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. 1998;43:815–25. · DOI · Paper page
  7. Schweers O, Schönbrunn-Hanebeck E, Marx A, Mandelkow E. Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for beta-structure. J Biol Chem. 1994;269:24290–7. · DOI
  8. Bunker JM, Kamath K, Wilson L, Jordan MA, Feinstein SC. FTDP-17 mutations compromise the ability of tau to regulate microtubule dynamics in cells. J Biol Chem. 2006;281:11856–63. · DOI
  9. Kadavath H, Hofele RV, Biernat J, Kumar S, Tepper K, Urlaub H, et al. Tau stabilizes microtubules by binding at the interface between tubulin heterodimers. Proc. Natl Acad. Sci. USA. 2015;112:7501–6. · DOI · Paper page
  10. Mahoney R, Ochoa Thomas E, Ramirez P, Miller HE, Beckmann A, Zuniga G, et al. Pathogenic tau causes a toxic depletion of nuclear calcium. Cell Rep. 2020;32:107900. · DOI
  11. Esteras N, Kopach O, Maiolino M, Lariccia V, Amoroso S, Qamar S, et al. Mitochondrial ROS control neuronal excitability and cell fate in frontotemporal dementia. Alzheimers Dement. 2021. https://doi.org/10.1002/alz.12394. · DOI
  12. Garcia ML, Cleveland DW. Going new places using an old MAP: tau, microtubules and human neurodegenerative disease. Curr Opin Cell Biol. 2001;13:41–48. · DOI
  13. Iovino M, Agathou S, Gonzalez-Rueda A, Del Castillo Velasco-Herrera M, Borroni B, Alberici A, et al. Early maturation and distinct tau pathology in induced pluripotent stem cell-derived neurons from patients with MAPT mutations. Brain: J Neurol. 2015;138:3345–59. · DOI · Paper page
  14. Ortiz-Virumbrales M, Moreno CL, Kruglikov I, Marazuela P, Sproul A, Jacob S, et al. CRISPR/Cas9-Correctable mutation-related molecular and physiological phenotypes in iPSC-derived Alzheimer’s PSEN2 (N141I) neurons. Acta Neuropathol. Commun. 2017;5:77. · DOI
  15. Sposito T, Preza E, Mahoney CJ, Seto-Salvia N, Ryan NS, Morris HR, et al. Developmental regulation of tau splicing is disrupted in stem cell-derived neurons from frontotemporal dementia patients with the 10 + 16 splice-site mutation in MAPT. Hum Mol Genet. 2015;24:5260–9. · DOI · Paper page
  16. Kopach O, Esteras N, Wray S, Rusakov DA, Abramov AY. Maturation and phenotype of pathophysiological neuronal excitability of human cells in tau-related dementia. J Cell Sci. 2020;133:10. · DOI · Paper page
  17. Esteras N, Rohrer JD, Hardy J, Wray S, Abramov AY. Mitochondrial hyperpolarization in iPSC-derived neurons from patients of FTDP-17 with 10+16 MAPT mutation leads to oxidative stress and neurodegeneration. Redox Biol. 2017;12:410–22. · DOI
  18. Verheyen A, Diels A, Reumers J, Van Hoorde K, Van den Wyngaert I, van Outryve d’Ydewalle C, et al. Genetically engineered iPSC-Derived FTDP-17 MAPT neurons display mutation-specific neurodegenerative and neurodevelopmental phenotypes. Stem Cell Rep. 2018;11:363–79. · DOI · Paper page
  19. Shi Y, Kirwan P, Livesey FJ. Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks. Nat Protoc. 2012;7:1836–46. · DOI · Paper page
  20. Kopach O, Rybachuk O, Krotov V, Kyryk V, Voitenko N, Pivneva T. Maturation of neural stem cells and integration into hippocampal circuits—a functional study in an in situ model of cerebral ischemia. J Cell Sci. 2018;131:1–10. · DOI
  21. Henneberger C, Bard L, Panatier A, Reynolds JP, Kopach O, Medvedev NI, et al. LTP induction boosts glutamate spillover by driving withdrawal of perisynaptic astroglia. Neuron. 2020;108:919–.e911. · DOI
  22. Kopach O, Zheng K, Rusakov DA. Optical monitoring of glutamate release at multiple synapses in situ detects changes following LTP induction. Mol Brain. 2020;13:39. · DOI
  23. Kopach O, Zheng K, Sindeeva OA, Gai M, Sukhorukov GB, Rusakov DA. Polymer microchamber arrays for geometry-controlled drug release: a functional study in human cells of neuronal phenotype. Biomater Sci. 2019;7:2358–71. · DOI
  24. Michaluk P, Heller JP, Rusakov DA. Rapid recycling of glutamate transporters on the astroglial surface. Elife. 2021. https://doi.org/10.7554/eLife.64714. · DOI
  25. Rusakov DA, Fine A. Extracellular Ca2+ depletion contributes to fast activity-dependent modulation of synaptic transmission in the brain. Neuron. 2003;37:287–97. · DOI
  26. Kalmbach BE, Buchin A, Long B, Close J, Nandi A, Miller JA, et al. h-Channels contribute to divergent intrinsic membrane properties of supragranular pyramidal. Neurons Hum versus Mouse Cereb Cortex Neuron. 2018;100:1194–.e1195.
  27. Nolan MF, Malleret G, Dudman JT, Buhl DL, Santoro B, Gibbs E, et al. A behavioral role for dendritic integration: HCN1 channels constrain spatial memory and plasticity at inputs to distal dendrites of CA1 pyramidal neurons. Cell. 2004;119:719–32.
  28. Magee JC. Dendritic hyperpolarization-activated currents modify the integrative properties of hippocampal CA1 pyramidal neurons. J Neurosci. 1998;18:7613–24. · DOI · Paper page
  29. Gawlak M, Szulczyk B, Berłowski A, Grzelka K, Stachurska A, Pełka J, et al. Age-dependent expression of Nav1.9 channels in medial prefrontal cortex pyramidal neurons in rats. Dev Neurobiol. 2017;77:1371–84. · DOI
  30. Cummins TR, Xia Y, Haddad GG. Functional properties of rat and human neocortical voltage-sensitive sodium currents. J Neurophysiol. 1994;71:1052–64. · DOI
  31. Hu W, Tian C, Li T, Yang M, Hou H, Shu Y. Distinct contributions of Na(v)1.6 and Na(v)1.2 in action potential initiation and backpropagation. Nat Neurosci. 2009;12:996–1002. · DOI · Paper page
  32. Zhang W, Tarutani A, Newell KL, Murzin AG, Matsubara T, Falcon B, et al. Novel tau filament fold in corticobasal degeneration. Nature. 2020;580:283–7. · DOI
  33. Mann DMA, Snowden JS. Frontotemporal lobar degeneration: pathogenesis, pathology and pathways to phenotype. Brain Pathol. 2017;27:723–36. · DOI
  34. Ling H, Kovacs GG, Vonsattel JP, Davey K, Mok KY, Hardy J, et al. Astrogliopathy predominates the earliest stage of corticobasal degeneration pathology. Brain: J Neurol. 2016;139:3237–52. · DOI
  35. Kovacs GG, Pittman A, Revesz T, Luk C, Lees A, Kiss E, et al. MAPT S305I mutation: implications for argyrophilic grain disease. Acta Neuropathol. 2008;116:103–18. · DOI
  36. Kovacs GG, Majtenyi K, Spina S, Murrell JR, Gelpi E, Hoftberger R, et al. White matter tauopathy with globular glial inclusions: a distinct sporadic frontotemporal lobar degeneration. J Neuropathol Exp Neurol. 2008;67:963–75. · DOI
  37. Iwasaki Y, Mori K, Ito M, Tatsumi S, Mimuro M, Kuwano R, et al. An autopsied case of unclassifiable sporadic four-repeat tauopathy presenting with parkinsonism and speech disturbances. Neuropathology. 2016;36:295–304. · DOI
  38. Nakano M, Riku Y, Nishioka K, Hasegawa M, Washimi Y, Arahata Y, et al. Unclassified four-repeat tauopathy associated with familial parkinsonism and progressive respiratory failure. Acta Neuropathol Commun. 2020;8:148. · DOI
  39. Ingram EM, Spillantini MG. Tau gene mutations: dissecting the pathogenesis of FTDP-17. Trends Mol Med. 2002;8:555–62. · DOI
  40. Medda X, Mertens L, Versweyveld S, Diels A, Barnham L, Bretteville A, et al. Development of a scalable, high-throughput-compatible assay to detect tau aggregates using iPSC-derived cortical neurons maintained in a three-dimensional culture format. J Biomol Screen. 2016;21:804–15. · DOI
  41. García-León JA, Cabrera-Socorro A, Eggermont K, Swijsen A, Terryn J, Fazal R, et al. Generation of a human induced pluripotent stem cell-based model for tauopathies combining three microtubule-associated protein TAU mutations which displays several phenotypes linked to neurodegeneration. Alzheimers Dement. 2018;14:1261–80. · DOI
  42. Fieblinger T, Graves SM, Sebel LE, Alcacer C, Plotkin JL, Gertler TS, et al. Cell type-specific plasticity of striatal projection neurons in parkinsonism and L-DOPA-induced dyskinesia. Nat Commun. 2014;5:5316. · DOI
  43. Bok E, Leem E, Lee BR, Lee JM, Yoo CJ, Lee EM, et al. Role of the lipid membrane and membrane proteins in tau pathology. Front Cell Dev Biol. 2021;9:653815. · DOI · Paper page
  44. Mari SA, Wegmann S, Tepper K, Hyman BT, Mandelkow EM, Mandelkow E, et al. Reversible cation-selective attachment and self-assembly of human tau on supported brain lipid membranes. Nano Lett. 2018;18:3271–81. · DOI
  45. Fanni AM, Vander Zanden CM, Majewska PV, Majewski J, Chi EY. Membrane-mediated fibrillation and toxicity of the tau hexapeptide PHF6. J Biol Chem. 2019;294:15304–17. · DOI
  46. Shrivastava AN, Redeker V, Pieri L, Bousset L, Renner M, Madiona K, et al. Clustering of Tau fibrils impairs the synaptic composition of α3-Na(+)/K(+)-ATPase and AMPA receptors. EMBO J. 2019;38:1–22. · DOI
  47. Solé L, Tamkun MM. Trafficking mechanisms underlying Na(v) channel subcellular localization in neurons. Channels (Austin). 2020;14:1–17. · DOI
  48. Estacion M, O’Brien JE, Conravey A, Hammer MF, Waxman SG, Dib-Hajj SD, et al. A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy. Neurobiol Dis. 2014;69:117–23. · DOI
  49. Lopez-Santiago LF, Yuan Y, Wagnon JL, Hull JM, Frasier CR, O’Malley HA, et al. Neuronal hyperexcitability in a mouse model of SCN8A epileptic encephalopathy. Proc Natl Acad Sci USA. 2017;114:2383–8. · DOI
  50. Wagnon JL, Barker BS, Ottolini M, Park Y, Volkheimer A, Valdez P, et al. Loss-of-function variants of SCN8A in intellectual disability without seizures. Neurol Genet. 2017;3:e170. · DOI
  51. Bezprozvanny I, Mattson MP. Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci. 2008;31:454–63. · DOI · Paper page
  52. Lim D, Rodríguez-Arellano JJ, Parpura V, Zorec R, Zeidán-Chuliá F, Genazzani AA, et al. Calcium signalling toolkits in astrocytes and spatio-temporal progression of Alzheimer’s disease. Curr Alzheimer Res. 2016;13:359–69. · DOI
  53. Gómez-Ramos A, Díaz-Hernández M, Rubio A, Miras-Portugal MT, Avila J. Extracellular tau promotes intracellular calcium increase through M1 and M3 muscarinic receptors in neuronal cells. Mol Cell Neurosci. 2008;37:673–81. · DOI
  54. Britti E, Ros J, Esteras N, Abramov AY. Tau inhibits mitochondrial calcium efflux and makes neurons vulnerable to calcium-induced cell death. Cell Calcium. 2020;86:102150. · DOI

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Metadata

Authors
Kopach, O., Esteras, N., Wray, S., Abramov, A. Y., & Rusakov, D. A.
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2021-07-17
Volume
12
Issue
8
ISSN
2041-4889
DOI
10.1038/s41419-021-04007-w
PMC
PMC8286258
Cited by
26
References
6
Language
en
Licence
Funders
  • Alzheimer’s Research UK (ARUKSRF2016B-2)
  • NIHR UCLH/UCL Biomedical Research Centre
  • RCUK | Engineering and Physical Sciences Research Council (EP/R024898/1)
  • Wellcome Trust (212251_Z_18_Z)
  • European Commission (NEUROTWIN grant 857562)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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