Nicotinic regulation of CREB activation in hippocampal neurons by glutamatergic and nonglutamatergic pathways.

Activity-dependent gene expression is essential for form and function in the nervous system. Best understood is the role of glutamatergic signaling in controlling such events, but nicotinic signaling can also regulate transcription. We show here that nicotine can alter gene expression in rat hippocampal neurons, as reflected by activation of the transcription factor CREB and appearance of the immediate early gene product c-Fos. The process depends on both CaM and MAP kinases and on calcium release from internal stores. Part of the nicotinic effect is mediated via glutamatergic transmission, even in the absence of action potentials. Voltage-gated calcium channels are not necessary for nicotine-induced activation of CREB in hippocampal neurons. The low levels of sustained nicotinic stimulation required for transcriptional effects are consistent with those likely to be achievable either by the normal septal cholinergic innervation of the hippocampus or by repeated tobacco usage.