, 2007; Hasselmo and Giocomo, 2006). In addition, nAChRs expressed in deep layer pyramidal neurons may contribute to direct Lenvatinib ic50 excitation of these cells (Bailey et al., 2010; Kassam et al., 2008; Poorthuis

et al., 2012). ACh also modulates synaptic transmission in cortical circuits (Figure 3). Activation of α4β2 nAChRs on thalamocortical terminals enhances glutamate release in both sensory and association cortex (Gil et al., 1997; Lambe et al., 2003; Oldford and Castro-Alamancos, 2003), whereas activation of mAChRs on terminals of parvalbumin-expressing interneurons decreases the probability of GABA release onto the perisynaptic compartment of pyramidal neurons and therefore reduces postsynaptic inhibition of pyramidal neurons (Kruglikov and Rudy, 2008). These interneurons normally decrease the response of cortical neurons to feed-forward excitation

(Gabernet et al., 2005; Higley and Contreras, 2006), and the reduction of GABA release from these interneurons by ACh therefore enhances the ability of thalamocortical inputs to stimulate pyramidal neuron firing (Kruglikov and Rudy, 2008). In contrast, mAChRs located on pyramidal cell axon terminals suppress corticocortical CH5424802 clinical trial transmission (Gil et al., 1997; Hsieh et al., 2000; Kimura and Baughman, 1997; Oldford and Castro-Alamancos, 2003). Moreover, the ACh-mediated increased excitability of dendrite-targeting interneurons described above likely contributes to reduced efficacy of intracortical communication. The simultaneous enhancement of feed-forward inputs from the thalamus through cholinergic actions on parvalbumin-positive interneurons and suppression of intracortical feedback inputs through effects on dendrite-targeting interneurons may increase the “signal-to-noise” ratio in cortical networks, making neurons more sensitive to external stimuli. In keeping with this view, mAChR activation strongly suppresses the spread of intracortical activity, leaving responses

to thalamic inputs relatively intact (Kimura et al., 1999). Intriguingly, in the prefrontal cortex, the expression of nAChRs in deep pyramidal cells others may produce layer-specific cholinergic modulation, selectively enhancing activity of output neurons (Poorthuis et al., 2012). 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, acting via M4 mAChRs, directly inhibits spiny stellate cells in somatosensory cortex receiving thalamic input (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).