Enhanced excitability of cortical neurons in low-divalent solutions is primarily mediated by altered voltage-dependence of voltage-gated sodium channels
Briana J Martiszus,
Timur Tsintsadze,
Wenhan Chang,
Stephen M Smith
Affiliations
Briana J Martiszus
Section of Pulmonary & Critical Care Medicine, VA Portland Health Care System, Portland, United States; Department of Medicine, Division of Pulmonary & Critical Care Medicine, Oregon Health & Science University, Portland, United States
Timur Tsintsadze
Section of Pulmonary & Critical Care Medicine, VA Portland Health Care System, Portland, United States; Department of Medicine, Division of Pulmonary & Critical Care Medicine, Oregon Health & Science University, Portland, United States
Wenhan Chang
Endocrine Research Unit, Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, United States
Section of Pulmonary & Critical Care Medicine, VA Portland Health Care System, Portland, United States; Department of Medicine, Division of Pulmonary & Critical Care Medicine, Oregon Health & Science University, Portland, United States
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.
