, 2009). A variety of mechanisms regulate this website cAMP signaling in layer III dlPFC spines. As mentioned above, the phosphodiesterase PDE4A, which catabolizes cAMP, is often localized next to HCN channels in spines and near the spine apparatus to regulate cAMP effects on internal Ca+2 release (Figure 5B; Paspalas et al., 2012). (In contrast, PDE4B is in the postsynaptic density and in dendrites, ibid.) It is likely that PDE4A is anchored to the correct location in the spine by the scaffolding

protein, DISC1 (Disrupted in Schizophrenia), as DISC1 tethers a variety of PDE4s (Murdoch et al., 2007) and colocalizes with PDE4A in layer III spines in monkey dlPFC (Figure 8C). DISC1 is also found next to HCN channels (Figure 5C)

and near the spine apparatus (Figure 8C) in monkey dlPFC layer III spines (Figure 5C), suggesting that a DISC1-PDE4A interactome is positioned to regulate both network gating and internal Ca+2 release. PDE4A may also be anchored to the spine apparatus by AKAP6 (A Kinase Anchor Protein 6, also known as AKAP100), which tethers cAMP-related proteins to endomembranes that harbor Ca+2 (Dodge-Kafka et al., 2008), such as the spine apparatus. Thus, PDE4A is positioned to reduce cAMP concentrations at several key sites in the spine, where it can decrease internal Ca+2 release and close HCN, KCNQ, and possibly SK channels. KCNQ channels are also closed by NSC 683864 mw cholinergic stimulation of M1 receptors within the same lipid raft as the channel itself (Oldfield et al., 2009), therefore SPTLC1 opposing cAMP-PKA actions on these channels. cAMP levels in the spine are also reduced by α2A-ARs, which inhibit cAMP generation. α2A-ARs colocalize with HCN channels

in layer III spines near the synapse and in the spine neck (Figures 5A; Wang et al., 2007). Stimulation of α2A-ARs, for example, with the α2A-AR agonist, guanfacine, specifically increases firing for the neuron’s preferred direction, thus enhancing mental representation (Wang et al., 2007). Conversely, blockade of α2A-ARs with yohimbine causes a complete collapse of dlPFC network firing (Li et al., 1999) that can be restored by blocking HCN channels (Figure 5D; Wang et al., 2007). Parallel effects are seen on cognitive behavior, where infusion of guanfacine directly into dlPFC improves working memory (Mao et al., 1999), and systemic administration of guanfacine improves a variety of PFC cognitive functions, including spatial working memory, behavioral inhibition, top-down regulation of attention, and rapid associative learning (reviewed in Arnsten, 2010). A recent study has shown that guanfacine improves impulse control by inhibiting responses to an immediate, small reward in order to wait over a delay for a larger reward (Kim et al., 2011).