Linking Microcircuit Dysfunction to Cognitive Impairment: Effects of Disinhibition Associated with Schizophrenia in a Cortical Working Memory Model

Disruption of the balance between excitation and inhibition in the prefrontal cortex is thought to underlie cognitive problems in schizophrenia. A computational model of spatial working memory showed that disinhibition—caused by perturbing NMDA receptors on interneurons—broadens the tuning of memory-related neural activity, leading to more variable and less precise stored information and a reduced ability to filter out distractions. This prediction was tested with behavioral data from humans given ketamine, which induces disinhibition, and ketamine increased errors as the model predicted. The model also showed that restoring excitation-inhibition balance could reverse these working memory deficits, pointing to new experimental approaches for studying memory problems in schizophrenia.

Study at a glance

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.