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. Author manuscript; available in PMC: 2016 Feb 1.
Published in final edited form as: Annu Rev Pharmacol Toxicol. 2016 Jan 6;56:339–360. doi: 10.1146/annurev-pharmtox-010715-103617

Figure 5.

Figure 5

DNC modulation in newly evolved dlPFC delay cell circuits. DNC in a mature, long, thin spine in layer III of the primate dlPFC alters synapse strength rapidly and reversibly to coordinate cognitive and arousal states. In contrast to traditional synapses, NMDAR-NR2Bs are localized exclusively in the PSD and are not extrasynaptic. These synapses have only a subtle AMPAR component, and the permissive excitation needed for NMDAR opening is instead mediated by cholinergic stimulation of nic-α7R (and possibly muscarinic M1R). Mechanisms that increase feedforward calcium-cAMP-PKA signaling (red, many engaged by stress) weaken synaptic connections by opening nearby K+ channels (HCN and KCNQ) on the spine head, neck, or both. In contrast, inhibiting feedforward calcium-cAMP-PKA signaling (green) strengthens connectivity and enhances delay cell firing. Loss of inhibition, e.g., through genetic insults to DISC1, may contribute to spine loss and impaired dlPFC function. The unique modulation of layer III dlPFC pyramidal cell synapses provides strategies for therapeutic targets for cognitive disorders. Abbreviations: AC, adenylyl cyclase; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; AR, adrenergic receptor; cAMP, cyclic adenosine monophosphate; D1R, dopamine D1 receptor; DISC1, Disrupted In SChizophrenia 1; dlPFC, dorsolateral prefrontal cortex; DNC, dynamic network connectivity; HCN, hyperpolarization-activated cyclic nucleotide gated channels; IP3R, inositol 1,4,5-trisphosphate receptor; KCNQ, potassium channel, voltage-gated, KQT-like subfamily; M1R, muscarinic M1 receptor; mGluR, metabotropic glutamate receptor; nic-α7R, nicotinic α7 receptor; NMDA, N-methyl-d-aspartate; NMDAR, NMDA receptor; PDE4A, phosphodiesterase 4A; PKA/PKC, protein kinase A/C.