Abstract

Synaptic plasticity, the fundamental mechanism underlying learning and memory, is critically dependent on the precise regulation of the intracellular ionic environment. This study investigates the distinct and synergistic contributions of monovalent ions, specifically sodium ($\text{Na}^+$) and potassium ($\text{K}^+$), and the divalent ion calcium ($\text{Ca}^{2+}$) to the induction and expression of long-term synaptic changes. Using electrophysiological recordings and pharmacological manipulations in hippocampal slice preparations, we examined the role of these ions in both long-term potentiation (LTP) and long-term depression (LTD). Our findings confirm the central role of $\text{Ca}^{2+}$ influx, primarily through NMDA receptors, as the key trigger for both forms of plasticity. However, we demonstrate that the dynamic regulation of intracellular $\text{Na}^+$ and $\text{K}^+$ homeostasis, mediated by $\text{Na}^+/\text{K}^+$-ATPase and various ion exchangers, significantly modulates the $\text{Ca}^{2+}$ signaling cascade. Specifically, $\text{Na}^+$ accumulation was found to enhance the magnitude of LTP, likely by reducing the driving force for $\text{Ca}^{2+}$ extrusion via the $\text{Na}^+/\text{Ca}^{2+}$ exchanger. Conversely, $\text{K}^+$ channel activity was shown to fine-tune neuronal excitability, indirectly setting the threshold for plasticity induction. These results highlight that synaptic plasticity is not solely governed by $\text{Ca}^{2+}$ but is a complex process intricately regulated by the concerted action of all major physiological ions, providing new targets for therapeutic intervention in cognitive disorders.