Calcium-dependent facilitation of P/Q-type calcium channels governs the polarity and magnitude of short-term synaptic plasticity

P/Q-type calcium channel (Cav2.1) is the major channel that mediates Ca ²⁺ influx during action potentials (APs) and evokes neurotransmitter release from presynaptic terminals. Repetitive activity induces its Ca ²⁺ -dependent facilitation (CDF) via binding of calmodulin (CaM) superfamily proteins to the IQ-like motif, specifically isoleucine (I) and methionine (M) sites, on the cytoplasmic c-terminus of Cav2.1. However, whether and how CDF contributes to short-term synaptic plasticity remains elusive. By recordings from the calyx of Held terminal in IQ-like motif point mutation knock-in mice (Cav2.1 IM-AA KI), we found that activity-dependent CDF is completely abolished, resulting in lower quantal output and shorter release time course as well as profound reductions in the magnitute of short-term facilitation and depression (STF and STD) in different Ca ²⁺ concentrations. Prolonging deactivation of Ca ²⁺ channels by broadening spike width normalizes quantal output and release time course in Cav2.1 IM-AA synapses, but does not fully rescue STF/STD. These results indicate that CDF of Cav2.1 channels governs the polarity and magnitude of short-term synaptic plasticity in fast-spiking central synapses.