Effects of chronic ketamine on hippocampal cross‐frequency coupling: implications for schizophrenia pathophysiology

Abstract

Disrupted neuronal oscillations have been identified as a potentially important biomarker for the perceptual and cognitive symptoms of schizophrenia. Emerging evidences suggest that interactions between different frequency bands, cross-frequency coupling (CFC), serve an important role in integrating sensory and cognitive information and may contribute to disease pathophysiology. In this study, we investigated the effects of 14-day consecutive administration of ketamine (30 mg/kg i.p.) vs. saline on alterations in amplitude and changes in the coupling of low-frequency (0-30 Hz) phase and high-frequency (30-115 Hz) amplitude in the CA1 hippocampus of Long Evans rats. Intracranial electrode recordings were conducted pre- and post-injection while the animals performed a foraging task on a four-arm rectangular maze. Permutation analysis of frequency band-specific change in amplitudes revealed between-group differences in theta (6-12 Hz) and slow gamma (25-50 Hz) but not fast gamma (65-100 Hz) bands at both slow and fast speeds. Chronic ketamine challenge resulted in decreased coupling (pre to post) at slow speeds but increased coupling at faster speeds, compared to either no or modest increased coupling in the saline group. These results demonstrate that chronic ketamine administration alters the interaction of low-frequency phase and high-frequency oscillations chronically and that such coupling varies as a function of locomotive speed. These findings provide evidence for the potential relevance of CFC to the pathophysiology of schizophrenia.

Long-term potentiation prevents ketamine-induced aberrant neurophysiological dynamics in the hippocampus-prefrontal cortex pathway in vivo

“…In freely moving animals, it was shown that acute ketamine can increase cross-frequency coupling between gamma activity and theta oscillations in the hippocampus of rats 16 . Chronic ketamine treatment also causes long-term alterations on theta-gamma CFC depending on the behavioral state 64 . Theta oscillations are prominent during exploratory activity 65 and theta-gamma CFC has been related to working memory and memory consolidation mechanisms [66][67][68] .…”

Orchestration of brain oscillations: principles and functions

“…Michaels et al . () document the changes to cross‐frequency coupling (CFC) and behavior in a rodent schizophrenia model (chronic ketamine administration) to start looking into the potential relevance of CFC in the pathophysiology of the psychoses. In a provocative piece, Klimesch () explores the frequency architecture of brain oscillations, specifically detailing cross‐frequency coupling principles, and extending this notion to mind‐body interactions where he asks if oscillatory‐like motor activity is simply another version of communication across systems that is governed by coupled oscillators.…”

Parvalbumin Cell Ablation of NMDA-R1 Leads to Altered Phase, But Not Amplitude, of Gamma-Band Cross-Frequency Coupling

“…A similar need for additional studies surrounds the preclinical observations of altered gamma-band PAC in mouse models relevant to ASD. Several recent preclinical studies report alterations to the strength of task-related gammaband PAC in murine models relevant to ASD (Cao et al, 2018;Michaels et al, 2018;Radwan et al, 2016), but the changes are complex and potentially not consistent. Separately RS theta to high-gamma PAC appears decreased in mice that have a genetic insult relevant to ASD (Port et al, 2017b).…”

“…Several studies have investigated murine models of relevance to ASD for alterations to the strength (amplitude) of task-related gamma-band PAC. Although these studies do report altered strength of gamma-band PAC in these mice as compared with either WT (Radwan et al, 2016) or before pharmacological insult (Michaels et al, 2018), the changes are complex and potentially inconsistent. Spontaneous RS gamma-band PAC has also been examined in a mouse model relevant to ASD, although the exact interpretation of such a ''resting'' period in mice is frequently disputed.…”