Ketamine alters oscillatory coupling in the hippocampus

Blocking NMDA receptors with ketamine alters how different brain rhythms interact in the hippocampus, a region critical for memory and attention. In awake rats, ketamine (25, 50, and 75 mg/kg) increased fast brain oscillations (gamma and high-frequency oscillations) across all layers of the CA1-dentate axis, while changes in slower theta waves depended on location. Ketamine also increased phase coherence of fast oscillations across hippocampal layers. The coupling between theta waves and fast oscillations changed in a dose-dependent way: theta-high-frequency coupling increased at all doses, but theta-gamma coupling increased only at the lowest dose and was disrupted at the highest dose. These findings indicate that NMDA receptor blockade disrupts neural coordination patterns linked to cognitive functions impaired in schizophrenia.

Study at a glance

Abstract

Recent studies show that higher order oscillatory interactions such as cross-frequency coupling are important for brain functions that are impaired in schizophrenia, including perception, attention and memory. Here we investigated the dynamics of oscillatory coupling in the hippocampus of awake rats upon NMDA receptor blockade by ketamine, a pharmacological model of schizophrenia. Ketamine (25, 50 and 75 mg/kg i.p.) increased gamma and high-frequency oscillations (HFO) in all depths of the CA1-dentate axis, while theta power changes depended on anatomical location and were independent of a transient increase of delta oscillations. Phase coherence of gamma and HFO increased across hippocampal layers. Phase-amplitude coupling between theta and fast oscillations was markedly altered in a dose-dependent manner: ketamine increased hippocampal theta-HFO coupling at all doses, while theta-gamma coupling increased at the lowest dose and was disrupted at the highest dose. Our results demonstrate that ketamine alters network interactions that underlie cognitively relevant theta-gamma coupling.