Kv4.2 regulates basal synaptic strength by inhibiting R-type calcium channels in the hippocampus

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 Kv4.2-specific antibody (anti-Kv4.2) into hippocampal neurons of mouse 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 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 kinase 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 inhibition of RTCCs. Significance Statement Synaptic transmission is mediated primarily by AMPA receptors (AMPARs) and there has been considerable interest in elucidating the mechanisms underlying their recruitment during activity-dependent synaptic strengthening. However, the mechanism by which basal synaptic strength is regulated remains elusive. Here, we show that blocking postsynaptic Kv4.2 enhances AMPAR-mediated currents in hippocampal neurons, and that this enhancement is mediated by the signaling mechanisms involving R-type Ca 2+ channels, protein kinases A and C. Importantly, Kv4.2 inhibition did not occlude activity-dependent synaptic potentiation, suggesting its specific influence in regulating synaptic AMPARs under basal conditions. Thus, our study highlights the critical function of Kv4.2 in regulating Ca 2+ signaling at subthreshold potentials, thereby regulating basal synaptic strength.