Loss of CaV1.3 RNA editing enhances mouse hippocampal plasticity, learning, and memory

L-type Ca(V)1.3 calcium channels are expressed on the dendrites and soma of neurons, and there is a paucity of information about its role in hippocampal plasticity. Here, by genetic targeting to ablate Ca(V)1.3 RNA editing, we demonstrate that unedited Ca(V)1.3(Delta ECS) mice exhibited improved learning and enhanced long-term memory, supporting a functional role of RNA editing in behavior. Significantly, the editing paradox that functional recoding of Ca(V)1.3 RNA editing sites slows Ca2+-dependent inactivation to increase Ca2+ influx but reduces channel open probability to decrease Ca2+ influx was resolved. Mechanistically, using hippocampal slice recordings, we provide evidence that unedited Ca(V)1.3 channels permitted larger Ca2+ influx into the hippocampal pyramidal neurons to bolster neuronal excitability, synaptic transmission, late long-term potentiation, and increased dendritic arborization. Of note, RNA editing of the Ca(V)1.3 IQ-domain was found to be evolutionarily conserved in mammals, which lends support to the importance of the functional recoding of the Ca(V)1.3 channel in brain function.

Automated summary

This study found that unedited Ca(V)1.3 calcium channels enhance long-term memory and learning, playing an important role in hippocampal plasticity. The study also resolved the editing paradox of functional recoding of Ca(V)1.3 RNA editing sites.