Epub – Neuropsychopharmacology
Mechanisms underlying dorsolateral prefrontal cortex contributions to cognitive dysfunction in schizophrenia

July 20, 2021

Smucny J, Dienel SJ, Lewis DA, Carter CS

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.

Smucny J, Dienel SJ, Lewis DA, Carter CS. Mechanisms underlying dorsolateral prefrontal cortex contributions to cognitive dysfunction in schizophrenia. Neuropsychopharmacology. 2021 Jul 20. doi: 10.1038/s41386-021-01089-0. [Epub ahead of print] PubMed PMID: 34285373 Review.


Translational Neuroscience Program

Understanding the Brain
to Improve Mental Health





© 2023 University of Pittsburgh


Assistant Director


University of Pittsburgh
3811 O'Hara Street, BST W1651
Pittsburgh, PA 15213


University of Pittsburgh
Department of Psychiatry

W1651 Biomedical Science Tower
203 Lothrop Street
Pittsburgh, PA 15213

Bridgeside Point II, Suite 223
450 Technology Drive
Pittsburgh, PA 15219