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bioRxiv · 10.64898/2025.12.07.692819

Divalent cation depletion enhances neuronal excitability through CaSR-dependent modulation of threshold channels

Mylonaki, K.·Alvarez-Saavedra, M. A.·Russier, M.·Debanne, D.·Incontro, S.
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Abstract

External calcium ([Ca{superscript 2}]{square}) and magnesium ([Mg{superscript 2}]{square}) concentrations fluctuate across physiological and pathological brain states. For example, [Ca{superscript 2}]{square} decreases during intense neuronal activity and epilepsy, whereas it rises during sleep. Similarly, [Mg{superscript 2}]{square} varies with the sleep/wake cycle and is reduced in epilepsy. Lowering either [Ca2+]e or [Mg2+]e increases intrinsic excitability and hyperpolarizes the action potential (AP) threshold, yet the underlying mechanisms remain unclear. Here, we confirm that reducing [Ca2+]e or [Mg2+]e enhances intrinsic excitability and hyperpolarizes the AP threshold of CA1 pyramidal neurons. Physiological reductions in [Mg{superscript 2}]{square} (0.8 [->] 0.4 mM) have minimal effect, whereas decreases from supraphysiological levels (2.0 [->] 0.4 mM) robustly increase excitability. Using pharmacology and CRISPR/Cas9 gene editing, we identify the calcium-sensing receptor (CaSR) as a key mediator of these effects. The calcilytic NPS-2143 mimics and largely occludes both the intrinsic excitability increase and the AP-threshold hyperpolarization, while genetic reduction of CaSR produces similar outcomes. We further show that AP-threshold hyperpolarization induced by low divalent cations involves both Kv1 and Nav1.2 channels. Together, these findings reveal CaSR as a critical link between external divalent cation levels and intrinsic neuronal excitability through the modulation of Kv1 and Nav channels.

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Mylonaki, K., Alvarez-Saavedra, M. A., Russier, M., Debanne, D., Incontro, S.. 2025-12-10. Divalent cation depletion enhances neuronal excitability through CaSR-dependent modulation of threshold channels. https://doi.org/10.64898/2025.12.07.692819

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