Synaptic activity controls localization and function of CtBP1 via binding to Bassoon and Piccolo

Persistent experience‐driven adaptation of brain function is associated with alterations in gene expression patterns, resulting in structural and functional neuronal remodeling. How synaptic activity—in particular presynaptic performance—is coupled to gene expression in nucleus remains incompletely understood. Here, we report on a role of CtBP1, a transcriptional co‐repressor enriched in presynapses and nuclei, in the activity‐driven reconfiguration of gene expression in neurons. We demonstrate that presynaptic and nuclear pools of CtBP1 are interconnected and that both synaptic retention and shuttling of CtBP1 between cytoplasm and nucleus are co‐regulated by neuronal activity. Finally, we show that CtBP1 is targeted and/or anchored to presynapses by direct interaction with the active zone scaffolding proteins Bassoon and Piccolo. This association is regulated by neuronal activity via modulation of cellular NAD/NADH levels and restrains the size of the CtBP1 pool available for nuclear import, thus contributing to the control of activity‐dependent gene expression. Our combined results reveal a mechanism for coupling activity‐induced molecular rearrangements in the presynapse with reconfiguration of neuronal gene expression. Synopsis In highly active neurons NADH abundance increases which leads to synaptic enrichment of CtBP1 due to a tighter association with its presynaptic anchor Bassoon/Piccolo. CtBP1‐mediated transcriptional repression of activity‐dependent genes is released. In conditions of low activity or low NADH levels, CtBP1 dissociates from Bassoon/Piccolo, becomes available for nuclear import and transcriptional repression. Neuronal activity controls synapto‐nuclear distribution of CtBP1. CtBP1 regulates the expression of neuronal activity‐dependent gene targets. Nuclear shuttling of CtBP1 is required for activity‐driven reconfiguration of neuronal gene expression. Bassoon and Piccolo anchor CtBP1 to presynapses via a direct interaction, which is modulated by activity and NAD/NADH levels. Bassoon and Piccolo restrain availability of CtBP1 for nuclear import and thereby its co‐repressor function. Graphical Abstract Synapto‐nuclear shuttling of the transcriptional co‐repressor CtBP1 is regulated by neuronal activity‐modulated NAD/NADH balance, and serves to couple synaptic activity with gene expression.