g., Figure 3A), where small changes in ionic conductance may be especially effective in transiently

gating inputs to the parent dendrite (Paspalas et al., 2012). Thus, DNC allows rapid and flexible alterations in network strength while maintaining a stable architecture. These mechanisms have been examined physiologically through the iontophoresis of minute amounts of drug onto dlPFC delay cells in monkeys performing the oculomotor working memory task (Figure 1B). The data have revealed that treatments that increase Ca+2-cAMP signaling rapidly decrease dlPFC delay cell firing, while those that VE822 inhibit Ca+2-cAMP signaling rapidly enhance task-related neuronal firing. Immunoelectron microscopy (immunoEM) has emphasized the importance of precise molecular localization and interactions and that it is not just the amount but the exact placement of molecular events that is needed for proper modulation

of cognitive circuits. A variety of DNC mechanisms serve to weaken synaptic efficacy DAPT mouse and induce a rapid (timescale of seconds) reduction in dlPFC firing (Figure 3B). These may be synergistic, feed-forward processes; for example, Ca+2 increases cAMP generation, and cAMP facilitates intracellular Ca+2 release from the spine apparata (indicated by asterisks) that are prominent in dlPFC long thin spines near the synapse (Soulsby and Wojcikiewicz, 2005). Calcium activation of protein kinase C may exacerbate this process, for example,

by uncoupling α2A-adrenergic receptors (α2-AR), which normally serve to inhibit cAMP signaling (Wang and Limbird, 3-mercaptopyruvate sulfurtransferase 2007; not shown in Figure 3). Calcium can build up in spines through a number of mechanisms, for example, through NMDA receptors (especially those with NR2B subunits) (Liu et al., 2007) and IP3-mediated internal Ca+2 release. Internal Ca+2 release is stimulated by NE α1-AR and by Gq-coupled metabotropic glutamate receptors (mGluR1α and/or mGluR5), which have been localized near the synapse in primate dlPFC spines (Figure 8E; Muly et al., 2003). mGluR generation of IP3 increases internal Ca+2 release from the spine apparatus; cAMP-PKA signaling can increase this process through phosphorylation of IP3 receptors (Soulsby and Wojcikiewicz, 2005). Calcium opens a variety of K+ channels; for example, SK channels, which can provide negative feedback for NMDA receptor excitation (Faber, 2010), reduce PFC cell firing (Hagenston et al., 2008) and impair working memory in rats (Brennan et al., 2008). SK channels have not yet been mapped in primate dlPFC but are likely to reside near the spine apparatus and on dendrites.