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

External calcium ([Ca ²⁺ ]□) and magnesium ([Mg ²⁺ ]□) concentrations fluctuate across physiological and pathological brain states. For example, [Ca ²⁺ ]□ decreases during intense neuronal activity and epilepsy, whereas it rises during sleep. Similarly, [Mg ²⁺ ]□ varies with the sleep/wake cycle and is reduced in epilepsy. Lowering either [Ca 2+ ] e or [Mg 2+ ] e increases intrinsic excitability and hyperpolarizes the action potential (AP) threshold, yet the underlying mechanisms remain unclear. Here, we confirm that reducing [Ca 2+ ] e or [Mg 2+ ] e enhances intrinsic excitability and hyperpolarizes the AP threshold of CA1 pyramidal neurons. Physiological reductions in [Mg ²⁺ ]□ (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.