The slow afterhyperpolarisation (sAHP) follows bursts of action potentials, lasts 1-3 s and underlies the late phase of spike frequency adaptation in cortical neurons. The sAHP is mediated by a calcium-activated potassium current (sIAHP) that is inhibited by different monoaminergic neurotransmitters leading to activation of an adenylyl cyclase resulting in an increase in cAMP and the subsequent activation of protein kinase A (PKA) (1). Our aim was to investigate the role of calcium stimulated adenylyl cyclases (AC1, AC8) in the modulation of sIAHP in CA1 pyramidal neurons. We compared wildtype (WT) and double knockout mice for both AC1 and AC8 (DKO) using the whole cell patch clamp technique in voltage- and current-clamp modes on hippocampal slices. The monoaminergic inhibition of both sIAHP and sAHP was examined through bath application of isoproterenol, serotonin and dopamine. We found that inhibition of sAHP and sIAHP by these neurotransmitters remains intact in DKO mice. High frequency stimulation of the Schaffer collateral pathway results in a transient inhibition of sAHP in CA1 pyramidal neurons due to calcium influx through NMDA receptors and activation of PKA (2). Therefore we investigated whether this pathway was disrupted in DKO mice. Recordings were performed at 30°C in the presence of the GABA(A) receptor antagonist picrotoxin (50 µM). Following high frequency stimulation of the Schaffer collateral pathway, the sAHP was transiently suppressed by 23.5±2.6% (N=11, n=14, p<0.0001) in the first six minutes following stimulation. This suppression was dependent on the activation of NMDA receptors (NMDAR), since it was abolished by the NMDAR antagonist AP5 (100 µM) applied 30 mins prior to stimulation (% sAHP suppression in AP5: –8.8±4.9% N=5, n=5, p<0.0001). The suppression of sAHP following high frequency synaptic stimulation was significantly attenuated in DKO mice (% sAHP suppression in DKO: 6.1±2.7%, N=6, n=10, p<0.0001). Similar results were obtained with another stimulation paradigm known to activate PKA (3) consisting of pairing 5Hz stimulation of the Schaffer collaterals to postsynaptic depolarisation. Also under these conditions, the suppression of the sAHP was significantly attenuated in DKO compared to WT mice (% sAHP suppression in WT: 42.9±5.2%, N=9, n=10; in DKO: 13.2±4.4, N=9, n=11; p<0.0001). Our results suggest that specific patterns of synaptic stimulation can lead to the activation of AC1/AC8 by calcium influx through NMDAR resulting in generation of cAMP, activation of PKA and subsequent reduction in sAHP.