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Mechanisms underlying dorsolateral prefrontal cortex contributions to cognitive dysfunction in schizophrenia

Abstract

Kraepelin, in his early descriptions of schizophrenia (SZ), characterized the illness as having “an orchestra without a conductor.” Kraepelin further speculated that this “conductor” was situated in the frontal lobes. Findings from multiple studies over the following decades have clearly implicated pathology of the dorsolateral prefrontal cortex (DLPFC) as playing a central role in the pathophysiology of SZ, particularly with regard to key cognitive features such as deficits in working memory and cognitive control. Following an overview of the cognitive mechanisms associated with DLPFC function and how they are altered in SZ, we review evidence from an array of neuroscientific approaches addressing how these cognitive impairments may reflect the underlying pathophysiology of the illness. Specifically, we present evidence suggesting that alterations of the DLPFC in SZ are evident across a range of spatial and temporal resolutions: from its cellular and molecular architecture, to its gross structural and functional integrity, and from millisecond to longer timescales. We then present an integrative model based upon how microscale changes in neuronal signaling in the DLPFC can influence synchronized patterns of neural activity to produce macrocircuit-level alterations in DLPFC activation that ultimately influence cognition and behavior. We conclude with a discussion of initial efforts aimed at targeting DLPFC function in SZ, the clinical implications of those efforts, and potential avenues for future development.

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Fig. 1: Findings from psychiatrically unaffected comparison individuals (left) and individuals with SZ (right) at multiple levels of resolution during cognitive control/working memory tasks.
Fig. 2: Summary of cellular and molecular alterations in the DLPFC of individuals diagnosed with SZ identified through postmortem studies.

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Authors JS, SJD, DAL, and CSC conceptualized and wrote the paper.

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Correspondence to David A. Lewis or Cameron S. Carter.

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Smucny, J., Dienel, S.J., Lewis, D.A. et al. Mechanisms underlying dorsolateral prefrontal cortex contributions to cognitive dysfunction in schizophrenia. Neuropsychopharmacol. (2021). https://doi.org/10.1038/s41386-021-01089-0

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