The Role of CaV2.1 Channel Facilitation in Synaptic Facilitation

SUMMARY Activation of CaV2.1 voltage-gated calcium channels is facilitated by preceding calcium entry. Such self-modulatory facilitation is thought to contribute to synaptic facilitation. Using knockin mice with mutated CaV2.1 channels that do not facilitate (Ca IM-AA mice), we surprisingly found that, under conditions of physiological calcium and near-physiological temperatures, synaptic facilitation at hippocampal CA3 to CA1 synapses was not attenuated in Ca IM-AA mice and facilitation was paradoxically more prominent at two cerebellar synapses. Enhanced facilitation at these synapses is consistent with a decrease in initial calcium entry, suggested by an action-potential-evoked CaV2.1 current reduction in Purkinje cells from Ca IM-AA mice. In wild-type mice, CaV2.1 facilitation during high-frequency action potential trains was very small. Thus, for the synapses studied, facilitation of calcium entry through CaV2.1 channels makes surprisingly little contribution to synaptic facilitation under physiological conditions. Instead, CaV2.1 facilitation offsets CaV2.1 inactivation to produce remarkably stable calcium influx during high-frequency activation.
Graphical Abstract
In Brief Weyrer et al. use Ca IM-AA mice in which CaV2.1 calcium channel facilitation is eliminated to study synaptic facilitation at hippocampal and cerebellar synapses. Under conditions of physiological temperature, external calcium, and presynaptic waveforms, facilitation of CaV2.1 channels is small and does not contribute to synaptic facilitation at these synapses.