Many neuronal processes require gene activation by synaptically evoked Ca²⁺ transients. Ca²⁺‐dependent signal pathways activate some transcription factors outright, but here we report that such signals also potentiate the activation of nuclear receptors by their cognate hormone, and of CBF1 by Notch, transcription factors hitherto not thought to be Ca²⁺‐responsive. This potentiation is occluded by histone deacetylase inhibition, indicating a mechanism involving inactivation of co‐repressors associated with these transcription factors. Synaptic activity, acting via the nuclear Ca²⁺‐dependent activation of CaM kinase IV, triggers the disruption of subnuclear domains containing class II histone deacetylases (HDACs) and silencing mediator of retinoic acid and thyroid hormone receptors (SMRT), a broad‐specificity co‐repressor which represses nuclear hormone receptors and CBF1. The sequential loss of class II HDACs and SMRT from the subnuclear domains, followed by nuclear export, is associated with disruption of SMRT interaction with its target transcription factors and sensitization of these factors to their activating signal. Counterbalancing these changes, protein phosphatase 1 promotes nuclear localization of SMRT and inactivation of nuclear receptors and CBF1. Thus, the synaptically controlled kinase‐phosphatase balance of the neuron determines the efficacy of SMRT‐mediated repression and the signal‐responsiveness of a variety of transcription factors.