The cellular mechanisms underlying the effects of ACh on cortical circuits have been investigated at many levels. Seminal studies revealed that ACh can produce biphasic changes in the activity of pyramidal neurons, the principal excitatory cells in the neocortex, comprising fast inhibition followed by a slow depolarization (McCormick and Prince, 1985, 1986). The fast inhibition is at least partially mediated by the actions of both nAChRs and mAChRs that increase the excitability and firing rates of dendrite-targeting GABAergic interneurons (Arroyo et al., 2012; Couey et al., 2007; Fanselow et al., 2008; Ferezou et al., 2002; Gulledge et al., 2007; Kawaguchi and Kubota, 1997). The slow depolarization is mediated by M1 mAChR-mediated closure of M-type (KCNQ) potassium channels in pyramidal neurons (Delmas and Brown, 2005) enhancing their excitability and reducing their spike frequency adaptation (Gulledge et al., 2007; Hasselmo and Giocomo, 2006). In addition, nAChRs expressed in deep layer pyramidal neurons may contribute to direct excitation of these cells (Bailey et al., 2010; Kassam et al., 2008; Poorthuis et al., 2012).
