biostudies-literatureZhai JNational University of SingaporeMinistry of Education - Singaporee2203883119https://www.ebi.ac.uk/biostudies/studies/S-EPMC9371748biostudies-literatureUnknown119(32)L-type Ca_V1.3 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_V1.3 RNA editing, we demonstrate that unedited Ca_V1.3^ΔECS 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_V1.3 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_V1.3 channProceedings of the National Academy of Sciences of the United States of AmericaLoss of Ca_V1.3 RNA editing enhances mouse hippocampal plasticity, learning, and memory.PMC9371748R185000271720SS)MOE2019-T2-2-024 (TWS)NUHSRO/2018/075/NUSMed-FoS/01(TWSWong RXSajikumar SLiang MCYeow SQZKrishna-K KYu WPHuang HZhai JSoong TWKoh JHNavakkode SfalseLoss of Ca_V1.3 RNA editing enhances mouse hippocampal plasticity, learning, and memory.L-type Ca_V1.3 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_V1.3 RNA editing, we demonstrate that unedited Ca_V1.3^ΔECS 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_V1.3 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_V1.3 chann2022-01-01T00:00:00Z2022 Aug2025-04-19T17:58:21.309Z2025-04-19T17:58:21.309ZS-EPMC93717483591416810.1073/pnas.2203883119