Although the cellular and synaptic effects of ACh described above provide a potential mechanism for the ability of ACh to increase signal detection and modulate sensory attention, a number of observations suggest that this simple model is incomplete. ACh directly inhibits spiny stellate cells in somatosensory cortex receiving thalamic input via M4 mAChRs (Eggermann and Feldmeyer, 2009). Furthermore, activation of M1 mAChRs hyperpolarizes pyramidal neurons via a mechanism dependent on fully-loaded internal calcium stores that occurs more quickly than the closure of M-type potassium channels (Gulledge et al., 2007; Gulledge and Stuart, 2005). Thus, the effect of ACh on the activity of cortical neurons clearly depends critically on the state of the neuron and the timing of ACh release. Neurons with depleted calcium stores would be more susceptible to ACh-induced depolarization via M4 mAChRs, whereas rapid inhibitory effects of ACh through M1 mAChRs would dominate in neurons with fully-replenished stores. Furthermore, studies showing that mAChR activation reduces cortico-cortical transmission have relied on electrical stimulation to evoke glutamate release, leaving the identity of the activated presynaptic terminals ambiguous. It is possible
