Transcription factors are rapidly and transiently induced in brain by excitatory stimuli and may be important in coordinating changes in gene expression underlying neuronal plasticity. In contrast to their transient induction after stimulation, certain transcription factors display stable, relatively high basal levels of expression in brain. Here we demonstrate that this "constitutive" expression of the transcription factor zif268 in cortex is driven by natural synaptic activity. Blockade of afferent visual activity with intraocular injections of tetrodotoxin results in rapid, dramatic reductions of Zif268 mRNA and immunoreactivity in visual cortex. Moreover, dark-adaptation for several days lowers zif268 expression in visual cortex, and expression rapidly returns to control levels upon subsequent light exposure. Several other transcription factors, which are induced in cortical neurons by excitatory stimuli, appear less responsive to changes in natural sensory input. These studies suggest that transcription factors play a role not only in responses to artificial stimuli but also in the normal maintenance of cortical physiology. Anatomic markers for zif268 may be useful in mapping normal cortical activity in brain.