Effects of ketamine on frontoparietal interactions during working memory in macaque monkeys

Schizophrenia involves disrupted communication between brain regions. Low doses of the NMDA receptor antagonist ketamine produce schizophrenia-like symptoms and cognitive deficits, including impaired working memory. This study recorded neural activity in the lateral prefrontal cortex and posterior parietal cortex of macaque monkeys performing a working memory task. Ketamine impaired rule coding in single neurons during the delay period, reduced low-frequency oscillations in the parietal cortex, and weakened task-related connectivity between frontal and parietal regions in both directions. It also reduced interareal coherence between spiking and low-frequency oscillations. The findings support the use of acute NMDA receptor antagonists to model dysconnection and explore new treatments for schizophrenia.

Study at a glance

Abstract

Schizophrenia is known as a syndrome of dysconnection among brain regions. As a model for this syndrome, low doses of N-methyl-D-aspartate (NMDA) receptor antagonists, such as ketamine, produce schizophrenia-like symptoms and cognitive deficits in healthy humans and animals. One of such deficits is impaired working memory, a process that engages an extended network of both frontal and parietal areas. While ketamine is known to disrupt working memory by altering both spiking and oscillatory activities in the lateral prefrontal cortex (lPFC), it remains unknown whether NMDA receptor antagonists also produce frontoparietal dysconnection during working memory processes. Here, we simultaneously recorded both single unit activities and local field potentials from lPFC and posterior parietal cortex (PPC) in macaque monkeys during a rule-based working memory task. Like previous work in the lPFC alone, we found that ketamine compromised delay-period rule coding in single neurons and reduced low-frequency oscillations in the PPC. Furthermore, ketamine reduced task-related connectivity in both fronto-parietal and parieto-frontal directions. Consistent with this, ketamine also weakened interareal coherence between spiking and low-frequency oscillatory activities. Our findings demonstrate the utility of acute NMDA receptor antagonist in simulating a syndrome of dysconnection and support this model in its potential for the exploration of novel treatment strategies for schizophrenia.