Executive Function, Neural Circuitry, and Genetic Mechanisms in Schizophrenia

Abstract

After decades of research aimed at elucidating the pathophysiology and etiology of schizophrenia, it has become increasingly apparent that it is an illness knowing few boundaries. Psychopathological manifestations extend across several domains, impacting multiple facets of real-world functioning for the affected individual. Even within one such domain, arguably the most enduring, difficult to treat, and devastating to long-term functioning – executive impairment – there are not only a host of disrupted component processes, but also a complex underlying dysfunctional neural architecture. Further, just as implicated brain structures (e.g., dorsolateral prefrontal cortex) via postmortem and neuroimaging techniques continue to demonstrate alterations in multiple, interacting signaling pathways, so too does evolving understanding of genetic risk factors suggest multiple molecular entry points to illness liability. With this expansive network of interactions in mind, the present chapter takes a systems-level approach to executive dysfunction in schizophrenia, by identifying key regions both within and outside of the frontal lobes that show changes in schizophrenia and are important in cognitive control neural circuitry, summarizing current knowledge of their relevant functional interactions, and reviewing emerging links between schizophrenia risk genetics and characteristic executive circuit aberrancies observed with neuroimaging methods.

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

“…This differential expression pattern may be inherent to the physiological circuits and inputs for each region. For example, connectivity deficits between the DLPFC and other neocortical structures have been well documented, where abnormal DLPFC activation significantly correlates with other cortical regions (Eisenberg and Berman, 2010). Additionally, communication between the ACC and DLPFC appears to be abnormal.…”

“…Additionally, communication between the ACC and DLPFC appears to be abnormal. ACC projections to the supragranular layers of the DLPFC are implicated because of their greater inhibition of the DLPFC (Eisenberg and Berman, 2010). Thus, the inherent connectivity and input of each region may be the mitigating factor behind the differential findings.…”

Impaired planning in Parkinson's disease is reflected by reduced brain activation and connectivity

“…Neuroimaging studies have consistently shown that this task causes robust activation of the bilateral dorsolateral prefrontal cortex, inferior parietal cortex, and the caudate nucleus in healthy populations [Boghi et al, 2006; Dagher et al, 1999; van den Heuvel et al, 2003]. Therefore, the ToL task is a well‐suited paradigm to probe CSTC and fronto‐parietal functioning in psychiatric and neurological disorders characterized by fronto‐striatal and fronto‐parietal failure, such as obsessive‐compulsive disorder [van den Heuvel et al, 2005] and related anxiety disorders [van den Heuvel et al, 2011], schizophrenia [Eisenberg and Berman, 2010], and PD [Owen, 2004; Williams‐Gray et al, 2007]. With our study we sought to expand upon previous findings by using cross‐sectional neuroimaging, combining task‐related activation, network connectivity, and performance over time.…”

Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

“…To investigate whether NRG1β affects Src-induced enhancement of synaptic NMDARs in another brain region implicated in the pathogenesis of schizophrenia, we studied the prefrontal cortex 43,49,50 . In acute slices from the medial prefrontal cortex, we evoked NMDAR EPSCs in layer V pyramidal neurons by stimulating the corticocortical neurons and afferents in layers II and III while pharmacologically blocking AMPA and GABA receptors.…”