Genetic studies have also found insults to VIPR2 (vasoactive selleck compound intestinal polypeptide receptor 2), which would increase cAMP signaling (Levinson et al., 2011; Vacic et al., 2011), and alterations in a primate-specific, cAMP-regulated potassium channel, KCNH2, (Huffaker et al., 2009); these proteins are not shown in Figure 8, as immunoEM has yet to localize their subcellular distribution in dlPFC. Thus, a

variety of different genetic insults could all lead to the same phenotype of dysregulated Ca+2-cAMP signaling and weakened layer III dlPFC pyramidal cell connections. These findings would also explain why stress is such an important factor in precipitating the onset of symptoms in this illness. Adolescence is a period of great vulnerability for the onset of serious mental illness, and it is a time of synaptic pruning and reorganization in PFC. Increased vulnerability may also arise from increased DA innervation of layer III in the primate dlPFC during adolescence, which SP600125 manufacturer may further drive dysregulated stress signaling pathways in dlPFC (Rosenberg and Lewis, 1995). It is possible that these actions contribute to dlPFC gray matter loss at onset of illness. In addition to weakening connections in layer III microcircuits, increased DA actions may alter the feedback (corollary discharge) from D2R-modulated layer

V response cells in dlPFC (Wang et al., 2004). D2R stimulation alters the timing and magnitude of response cell firing, which in human subjects may contribute to symptoms of hallucinations (Ford et al., 2002) and delusions (Corlett et al., 2007). These cortical errors would be magnified by increased DA D2R signaling in caudate (Laruelle et al., 1996), weakening inhibition of inappropriate network activity by the striatal indirect pathway (Arnsten, 2011). Disruptions in PFC-striatal operations, compounded with insults to the

formation of circuits during development (Brandon and Sawa, 2011), would lead to profound cognitive disorder (Arnsten, 2011). Research on the primate dlPFC has revealed that the highly evolved microcircuits underlying representational knowledge are modulated in a unique manner, different ADAMTS5 from sensory/motor and subcortical circuits. These differences must be respected if we are to understand the neurobiology underlying higher cognitive disorders and thus create effective treatments. We need to understand how genetic and environmental alterations in higher cognitive circuits impact their physiological integrity and learn how to substitute for insults by identifying targets in the same subcellular compartment that can restore function. The success of guanfacine in treating PFC disorders serves as a proof of concept, showing that understanding the unique modulation of higher cortical circuits can lead to effective treatments for humans.