Enhanced excitability of cortical neurons in low-divalent solutions is primarily mediated by altered voltage-dependence of voltage-gated sodium channels

• Published in: eLife Vol. 10
• Main Authors: Martiszus, Briana J, Tsintsadze, Timur, Chang, Wenhan, Smith, Stephen M
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 11-05-2021; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Action potential; Action Potentials; Animals; calcium; Calcium (extracellular); Calcium channels; Calcium channels (voltage-gated); Calcium-sensing receptors; CaSR; Cells, Cultured; Channel gating; Depolarization; Excitability; Experiments; Female; Genotype & phenotype; Ion Channel Gating - physiology; Male; Membrane potential; Mice; Mice, Inbred C57BL; NALCN; Neurons; Neurons - metabolism; Neurons - physiology; Neuroscience; Physiology; Receptors, Calcium-Sensing; Smith, Stephen M; Sodium; Sodium channels (voltage-gated); Surface charge; VGSC; Voltage-Gated Sodium Channels - genetics; Voltage-Gated Sodium Channels - metabolism; mouse; CaSR; calcium; excitability; neuroscience; VGSC; surface charge; NALCN
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.67914

Increasing extracellular [Ca2+] ([Ca2+]o) strongly decreases intrinsic excitability in neurons but the mechanism is unclear. By one hypothesis, [Ca2+]o screens surface charge, reducing voltage-gated sodium channel (VGSC) activation and by another [Ca2+]o activates Calcium-sensing receptor (CaSR) closing the sodium-leak channel (NALCN). Here we report that neocortical neurons from CaSR-deficient (Casr-/-) mice had more negative resting potentials and did not fire spontaneously in reduced divalent-containing solution (T0.2) in contrast with wild-type (WT). However, after setting membrane potential to -70 mV, T0.2 application similarly depolarized and increased action potential firing in Casr-/- and WT neurons. Enhanced activation of VGSCs was the dominant contributor to the depolarization and increase in excitability by T0.2 and occurred due to hyperpolarizing shifts in VGSC window currents. CaSR deletion depolarized VGSC window currents but did not affect NALCN activation. Regulation of VGSC gating by external divalents is the key mechanism mediating divalent-dependent changes in neocortical neuron excitability.