Reciprocal interaction of serotonin and neuronal activity in regulation of cAMP-responsive element-dependent gene expression

Neuronal activity triggers multiple signal transduction pathways and potently regulates gene expression in the brain. In the central nervous system, in addition to the synaptic input, neurons are subject to neuromodulatory influences that can activate the same signaling elements. However, the principles that govern the interaction of neuromodulators and neuronal activity in the regulation of gene expression are unclear. Here, we examine how serotonergic neuromodulation interacts with neuronal activity in the regulation of gene expression in hippocampal neurons. We show that cAMP-response element binding protein (CREB) phosphorylation and gene expression were stimulated by serotonin (5-HT) in the absence of neuronal activity. In contrast, in the presence of neuronal activity, 5-HT inhibited gene expression down to the baseline, although neuronal activity alone was sufficient to maximally activate gene expression. The ability of 5-HT to stimulate CREB phosphorylation in the absence of neuronal activity or inhibit CREB phosphorylation during activity was due to a tight balance between protein kinases and phosphatases that could be physiologically tilted by different serotonergic receptors or exogenously influenced by phosphatase and kinase inhibitors. Taken together, these results suggest a reciprocal inhibitory interaction between neuronal activity and 5-HT in the regulation of cAMP response element-dependent gene expression in hippocampal neurons.