Persistent experience-induced changes in brain performance are connected with reconfiguration of neuronal gene expression patterns, which lead to structural and functional alterations of brain circuits. How signals about neuronal activity levels (especially in the axons and presynapses) are converted into changes of gene expression in neuronal nuclei is still poorly understood. In this talk I will present our data pointing to a novel neuronal function of C-terminal binding protein 1 (CtBP1) in the activity-induced presynapse to nucleus signaling, which controls expression of neuronal activity-regulated genes. CtBP1 is a nuclear co-repressor with distinct localization to presynaptic compartment and to nuclei in neurons. We found that synaptic retention and nuclear abundance of CtBP1 are tightly coupled and regulated by neuronal activity. The nuclear shuttling of CtBP1 requires its active retrograde transport mediated by axonal importin beta and karyopherin-mediated nuclear import and export and critically influences expression of activity-regulated genes. Presynaptic anchoring of CtBP1 is mediated by its direct interaction with active zone proteins Bassoon and Piccolo. This association is regulated by neuronal activity via modulation of the cellular NAD/NADH balance. The synaptic retention of CtBP1 restrains the availability of CtBP1 for nuclear import and thereby contributes to the regulation of activity-dependent gene expression in neurons. This novel CtBP1-signalling pathway links the synaptic function, cellular metabolic state and expressional control of neuronal activity-regulated genes, provides new mechanism for experience-driven shaping of neuronal circuits and is likely involved in neuropathology induced by epilepsy-, stroke- or neurodegeneration-linked neuronal damage. FINANCIAL SUPPORT: DFG FE1335-1, SFG779 A06, GRK 1167, the Leibniz Association (SAW 2013-15) and Center for Brain Behavioral Studies NN5 (ZS/2016/04/78120).
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