Kv4.2 subunits, which mediate transient A-type K current, are crucial in regulating neuronal excitability and synaptic responses within the hippocampus. While their contribution to activity-dependent regulation of synaptic response is well-established, the impact of Kv4.2 on basal synaptic strength remains elusive. To address this gap, we introduced a Kv4.2-specific antibody (anti-Kv4.2) into hippocampal neurons of mice of both sexes to selectively inhibit postsynaptic Kv4.2, enabling direct examination of its impact on excitatory postsynaptic potentials (EPSPs) and currents (EPSCs) during basal synaptic activity. Our results demonstrated that blocking Kv4.2 significantly enhanced the amplitude of EPSPs. This amplification was proportional to the increase in the amplitude of EPSCs, which, in turn, correlated with the expression level of Kv4.2 in the dendritic regions of the hippocampus. Furthermore, the anti-Kv4.2-induced increase in EPSC amplitude was associated with a decrease in the failure rate of EPSCs evoked by minimal stimulation, suggesting that blocking Kv4.2 facilitates the recruitment of AMPA receptors to both silent and functional synapses to enhance synaptic efficacy. The anti-Kv4.2-induced synaptic potentiation was effectively abolished by intracellular 10 mM BAPTA or by blocking R-type calcium channels (RTCCs) and downstream signaling molecules, including protein kinases A and C. Importantly, Kv4.2 inhibition did not occlude further synaptic potentiation induced by high-frequency stimulation, suggesting that anti-Kv4.2-induced synaptic strengthening involves unique mechanisms that are distinct from long-term potentiation pathways. Taken together, these findings underscore the essential role of Kv4.2 in the regulation of basal synaptic strength, which is mediated by the inhibition of RTCCs.
