Details

Autor(en) / Beteiligte

• Zhai, Jing
• Navakkode, Sheeja
• Yeow, Sean Qing Zhang
• Krishna-K, Kumar
• Liang, Mui Cheng
• Koh, Joanne Huifen
• Wong, Rui Xiong
• Yu, Wei Ping
• Sajikumar, Sreedharan
• Huang, Hua
• Soong, Tuck Wah

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2022-08, Vol.119 (32), p.e2203883119-e2203883119

Ort / Verlag

National Academy of Sciences

Erscheinungsjahr

2022

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Adenosine-to-inosine RNA editing generates various levels of editing in a developmental and spatiotemporal manner. This posttranscriptional process can diversify protein functions or levels through recoding codons or through affecting alternative splicing or noncoding RNA binding. In mammals, including humans, the editome contains millions of editing sites. This paper focuses on the functional and neurophysiological significance of L-type voltage-gated calcium channel Ca V 1.3 RNA editing. It is not only evolutionarily conserved across species but also tunable in response to training in learning and memory. The unexpected role that the Ca V 1.3 channel plays in hippocampal learning and memory was also revealed as a result of a combination of gain of function in biophysical properties arising from the loss of Ca V 1.3 RNA editing . 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 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 V 1.3 RNA editing sites slows Ca 2+ -dependent inactivation to increase Ca 2+ influx but reduces channel open probability to decrease Ca 2+ influx was resolved. Mechanistically, using hippocampal slice recordings, we provide evidence that unedited Ca V 1.3 channels permitted larger Ca 2+ 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.