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

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.

Altered global brain signal in schizophrenia

“…Other computational modeling and neurophysiological evidence using behaving monkeys (41) suggest that a reduction of local recurrent excitation could explain cognitive deficits associated with SCZ. Present results can be reconciled with these observations by considering excitation/inhibition balance (E/I balance) (42). Our modeling results suggest that in the resting state, SCZ is associated with an increased E/I balance of either local or long-range, which is in line with the hypothesis of prominent inhibitory deficits in chronic SCZ (43).…”

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

“…α5-NAM could be acutely efficient in certain cognitive tasks such as spatial reference [52] where disinhibition of pyramidal neurons may facilitate the acquisition of a mental spatial map. In contrast, an α5-PAM could be efficient in cognitive tasks (such as working memory) where increased inhibition of neuronal activity may reduce noise and interferences, and increase signal-to-noise ratio for incoming stimuli [53, 54], together strengthening the salient inputs that need to be kept for high-level performances [55]. This hypothesis on the roles of NAMs and PAMs will require further validation and side-by-side comparison in multiple cognitive tasks.…”

Functional hierarchy underlies preferential connectivity disturbances in schizophrenia

“…S12), illustrating the interplay between the model and experimental effects. The ability of biophysically based computational models to generate predictions across levels of experimental analysis (29,45,87) is especially critical for computational psychiatry applications in severe disorders, such as SCZ, which affect multiple interconnected pathways at the local circuit and systems levels. Collectively, this study establishes a proof-of-principle computational psychiatry approach whereby neurobiologically grounded modeling of clinical data can generate results that help explain multiple distinct clinical neuroimaging effects.…”