Coactivation of beta-adrenergic and cholinergic receptors enhances the induction of long-term potentiation and synergistically activates mitogen-activated protein kinase in the hippocampal CA1 region

Interactions between noradrenergic and cholinergic receptor signaling may b e important in some forms of learning. To investigate whether noradrenergic and cholinergic receptor interactions regulate forms of synaptic plasticit y thought to be involved in memory formation, we examined the effects of co ncurrent beta-adrenergic and cholinergic receptor activation on the inducti on of long-term potentiation (LTP) in the hippocampal CA1 region. Low conce ntrations of the beta-adrenergic receptor agonist isoproterenol (ISO) and t he cholinergic receptor agonist carbachol had no effect on the induction of LTP by a brief train of 5 Hz stimulation when applied individually but dra matically facilitated LTP induction when coapplied. Although carbachol did not enhance ISO-induced increases in cAMP, coapplication of ISO and carbach ol synergistically activated p42 mitogen-activated protein kinase (p42 MAPK ). This suggests that concurrent beta-adrenergic and cholinergic receptor a ctivation enhances LTP induction by activating MAPK and not by additive or synergistic effects on adenylyl cyclase. Consistent with this, blocking MAP K activation with MEK inhibitors suppressed the facilitation of LTP inducti on produced by concurrent beta-adrenergic and cholinergic receptor activati on. Although MEK inhibitors also suppressed the induction of LTP by a stron ger 5 Hz stimulation protocol that induced LTP in the absence of ISO and ca rbachol, they had no effect on LTP induced by high-frequency synaptic stimu lation or low-frequency synaptic stimulation paired with postsynaptic depol arization. Our results indicate that MAPK activation has an important, modu latory role in the induction of LTP and suggest that coactivation of noradr energic and cholinergic receptors regulates LTP induction via convergent ef fects on MAPK.