A commonly held understanding in neuroscience is that neurons can adapt their synaptic contacts in order to more efficiently encode information in the context of learning. And while there is no doubt that synaptic encoding is very important for this process, there are additional ways in which neurons can adapt themselves to generate a malleable output in response to incoming stimuli. One such way is to modulate a neurons excitability and shift the entire input-output response curve rather than modulating particular synaptic weights. Muscarinic acetylcholine receptors (mAChRs) inhibit small-conductance calcium activated K+ channels (SK channels) and can enhance synaptic weight via this mechanism. However, SK channels are also known to be regulated in activity-dependent plasticity of membrane excitability (the cell’s ‘intrinsic plasticity’). Initially, we investigated whether muscarinic activation can drive SK channel-dependent changes in intrinsic excitability in Layer II/III pyramidal neurons of primary somatosensory cortex (S1). To accomplish this, we utilized whole-cell patch-clamp recordings from these neurons in slice and monitored spiking responses over time to 500 ms depolarizing pulses that initially generate 4-8 spikes before any manipulations. Therefore, if the intrinsic plasticity of the cell were to shift, this could be detected by a decrease or increase in the overall number of spikes during these test pulses. Using this method, we found that brief bath application of the mAChR agonist oxotremorine-m (oxo-m) causes long-term enhancement of excitability in wild-type mice that is not observed in mice deficient of the SK2 isoform (SK2KO mice). It had been shown that mAChR activation could affect several cellular features through SK channels, but had not yet directly shown that it could enhance responses to incoming currents through SK2 channels in particular. Similarly, repeated injection of depolarizing current pulses (modeled off of Mahon & Charpier 2012) into the soma triggers a shift in intrinsic excitability that is absent from SK2KO mice and thus relies on these channels. When evaluating specifically how spiking phenotypes shift within a single stimulus sweep, we identified that spikes occur more quickly as the cell become more excitable in these conditions. Additionally, we monitored the proportion of spikes that occurred toward the back of an individual stimulus sweep and saw an increase in spiking in the late phase of the test pulses. This lowering of spike attenuation is consistent with SK channel modulation, which can have a 200 ms time constant to become fully activated and shunt off late spiking and produce an after-hyperpolarization. We next examined what intracellular pathways are responsible for the modulation of SK2 channels, and found depolarization-induced plasticity is prevented by bath application of the protein kinase A (PKA) inhibitor H89, and the casein kinase 2 (CK2) inhibitor TBB, respectively. These findings point toward a recruitment of two known signaling pathways in SK2 regulation: SK channel trafficking (PKA) and reduction of the calcium sensitivity and thus response of SK channels (CK2). Given these results, we also tested the effects of muscarinic activation via oxo-m with H89 in the bath, and found that while PKA was inhibited muscarinic receptors could not induce a change in plasticity. These results offer additional data to the controversial subject of how muscarinic signaling impacts SK channels, and supports two well founded mechanisms by which SK channels can be functionally downregulated. We also utilized mice with an inactivation of CaMKII (T305D mice) which have a mimicked permanent inhibitory phosphorylation of CaMKII. These mice were still able to shift their intrinsic excitability, along with their WT counterparts, even when the induction method required activation of synaptic contacts. Finally, we demonstrated that repeated injection of depolarizing pulses in the presence of oxo-m causes intrinsic plasticity that surpasses the plasticity amplitude reached by either manipulation alone. This showed that these methods of intrinsic plasticity induction can work together, and we have not hit a ceiling effect in our manipulations. Our findings in total demonstrate that muscarinic activation and increased activation of the soma enhances membrane excitability in layer II/III pyramidal neurons via a downregulation of SK2 channels.