A slow afterhyperpolarization (sAHP) follows bursts of action potentials in hippocampal pyramidal neurons and is mediated by a Ca2+-dependent K+ current known as sI(AHP). This current presents slow kinetics of activation and decay, with time constants in the range of seconds. The sI(AHP) is voltage-independent: its activation requires changes in the intracellular Ca2+ concentration generated by the opening of voltage-gated Ca2+ channels during action potentials. Calcium-induced calcium release from ryanodine-sensitive stores further contributes to the activity-dependent potentiation of this current. In hippocampal neurons, sI(AHP) can be easily distinguished from the SK-channel mediated I(AHP): the two currents present different kinetics, functional coupling to calcium sources and pharmacological profiles, with the bee-venom toxin apamin inhibiting I(AHP), but not sI(AHP). The sAHP is responsible for the late phase of spike frequency adaptation and leads to a strong reduction in action potential firing. A distinctive feature of sI(AHP) is its modulation by several neurotransmitters and second messenger pathways. In particular, various monoamine transmitters (noradrenaline, dopamine, histamine and serotonin) suppress sI(AHP) through a signaling pathway that involves cAMP as a second messenger and the activation of protein kinase A (PKA). Additionally, the sI(AHP) is tonically modulated by the basal level of activity of PKA and a serine/threonine protein phosphatase, suggesting that the sAHP channels might be part of a signalling complex. To identify the components of the signaling domains underlying the monoaminergic and basal modulation of sI(AHP), we first focused on specific adenylyl cyclases. In particular, we addressed the role of the calcium-stimulated adenylyl cyclases, AC1 and AC8, by using genetically modified mice lacking both AC1 and AC8 (DKO). Suppression of the sI(AHP) by beta-adrenergic receptor agonists and serotonin was similar in CA1 pyramidal neurons from wildtype and DKO mice. Activation of NMDA receptors by high frequency (100 Hz) synaptic stimulation used for the induction of long-term potentiation at the Schaffer collateral-CA1 synapse leads to a PKA-dependent, transient inhibition of the postsynaptic sAHP (1). The NMDA receptor-mediated suppression of sAHP is abolished in DKO mice. Similar results were obtained in response to a stimulation protocol pairing postsynaptic depolarization with 5 Hz presynaptic stimulation. We conclude that the sAHP channels might be part of distinct signalling domains in CA1 pyramidal neurons. The calcium-sensitive adenylyl cyclases AC1 and AC8 do not seem to be an essential component of the signalling complex utilized by some monoaminergic transmitters to suppress sI(AHP), but they are essential for the modulation of sAHP by NMDA receptors in response to synaptic stimuli that induce long-term synaptic plasticity.