Abstract

Synaptic plasticity, the ability of synapses to strengthen or weaken over time, is the fundamental cellular mechanism underlying learning and memory. A critical component of this process is the trafficking and functional modulation of $\alpha$-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. While most mature AMPA receptors are $\text{Ca}^{2+}$-impermeable due to the presence of the GluA2 subunit, a subset of $\text{Ca}^{2+}$-permeable AMPA receptors (CP-AMPARs), which lack GluA2, are transiently inserted into the postsynaptic membrane during the induction of certain forms of long-term potentiation (LTP). This study investigates the precise role and regulatory mechanisms of CP-AMPARs in the induction and expression of synaptic plasticity. Using electrophysiological recordings and pharmacological manipulation in a model system, we demonstrate that the transient presence of CP-AMPARs is essential for the initial phase of LTP, specifically by mediating a critical influx of $\text{Ca}^{2+}$. This $\text{Ca}^{2+}$ signal is necessary to activate downstream signaling cascades, such as $\text{Ca}^{2+}/\text{calmodulin-dependent}$ protein kinase II (CaMKII), which are required for the stable expression of plasticity. Furthermore, we show that the rapid removal of CP-AMPARs acts as a self-limiting mechanism, ensuring the precise temporal control of synaptic strength. These findings highlight CP-AMPARs as a key molecular switch in the dynamic regulation of excitatory synapses, offering a potential therapeutic target for disorders involving cognitive dysfunction.