Linking microcircuit dysfunction to cognitive impairment: Effects of disinhibition associated with schizophrenia in a cortical working memory model

John D. Murray, Alan Anticevic, Mark Gancsos, Megan Ichinose, Philip R. Corlett, John H. Krystal, Xiao Jing Wang

Research output: Contribution to journalArticle

Abstract

Excitation-inhibition balance (E/I balance) is a fundamental property of cortical microcircuitry. Disruption of E/I balance in prefrontal cortex is hypothesized to underlie cognitive deficits observed in neuropsychiatric illnesses such as schizophrenia. To elucidate the link between these phenomena, we incorporated synaptic disinhibition, via N-methyl-D-aspartate receptor perturbation on interneurons, into a network model of spatial working memory (WM). At the neural level, disinhibition broadens the tuning of WM-related, stimulus-selective persistent activity patterns. The model predicts that this change at the neural level leads to 2 primary behavioral deficits: 1) increased behavioral variability that degrades the precision of stored information and 2) decreased ability to filter out distractors during WM maintenance. We specifically tested the main model prediction, broadened WM representation under disinhibition, using behavioral data from human subjects performing a spatial WM task combined with ketamine infusion, a pharmacological model of schizophrenia hypothesized to induce disinhibition. Ketamine increased errors in a pattern predicted by the model. Finally, as proof-of-principle, we demonstrate that WM deteriorations in the model can be ameliorated by compensations that restore E/I balance. Our findings identify specific ways by which cortical disinhibition affects WM, suggesting new experimental designs for probing the brain mechanisms of WM deficits in schizophrenia.

Original languageEnglish (US)
Pages (from-to)859-872
Number of pages14
JournalCerebral Cortex
Volume24
Issue number4
DOIs
StatePublished - Apr 2014

Keywords

  • NMDAR hypofunction
  • disinhibition
  • prefrontal cortex
  • schizophrenia
  • working memory

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience

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