Comparison of the effects of acute and chronic administration of ketamine on hippocampal oscillations: relevance for the NMDA receptor hypofunction model of schizophrenia

Abstract

The proper organization and function of GABAergic interneuron networks is essential for many cognitive processes and abnormalities in these systems have been documented in schizophrenic patients. The memory function of the hippocampus depends on two major patterns of oscillations in the theta and gamma ranges, both requiring the intact functioning of the network of fast-firing interneurons expressing parvalbumin. We examined the ability of acute and chronic administration of NMDA receptor antagonists to recapitulate the oscillatory dysfunctions observed in schizophrenia. In freely moving rats, acute injection of MK801 or ketamine increased gamma power in both CA1 and dentate gyrus of the hippocampus. Theta peak shifted to higher frequencies whereas the average 5–10 Hz theta power decreased by 24% in CA1 and remained high in the dentate gyrus. Strong increase in CA1 gamma and decrease in theta power triggered by brainstem stimulation were found under urethane anesthesia. In contrast to acute experiments, chronic administration of ketamine caused a steady decline in both gamma and theta oscillations, 2–4 weeks after treatment. A further important difference between the two models was that the effects of acute injection were more robust than the changes after chronic treatment. Chronic administration of ketamine also lead to decrease in the number of detectable parvalbumin interneurons. Histological examination of interindividual differences indicated however that within the ketamine treated group a further decrease in parvalbumin neurons correlated with strengthening of oscillations. The findings are consistent with abnormalities of oscillations in human schizophrenia and further validate the NMDA receptor hypofunction hypothesis.

Differential Effects of an NR2B NAM and Ketamine on Synaptic Potentiation and Gamma Synchrony: Relevance to Rapid-Onset Antidepressant Efficacy

“…In the present study ketamine impaired auditory gating, in line with published findings (Kocsis et al, 2013). It has also been demonstrated that ketamine enhances gamma-band power both in experimental animals and humans, a response which is frequently referred to as aberrant gamma activity, and which is considered a possible factor in the psychotomimetic effects of ketamine (Kittelberger et al, 2012;Kocsis et al, 2013;Pinault, 2008). Consistent with these previous findings, in the present study Neurophysiological effects of an NR2B NAM and ketamine D Nagy et al ketamine increased gamma power multiple times over baseline values compared with vehicle-treated rats in both cortical and hippocampal regions.…”

Reverse Translation of Clinical Electrophysiological Biomarkers in Behaving Rodents under Acute and Chronic NMDA Receptor Antagonism

“…However, we did find a significant decrease in total broadband power after chronic MK-801, but not PTX, suggesting that chronic MK-801may produce a blunting of oscillatory power across in a nonfrequency-specific manner. This is in line with previous studies showing reduced theta and gamma power after chronic or subchronic NMDAR antagonism (Featherstone et al, 2012;Kittelberger et al, 2012). Interestingly, these studies detected oscillatory effects several weeks or months after cessation of chronic NMDAR antagonism, suggesting that effects of chronic NMDAR antagonism may be long lasting.…”

Rapid Antidepressant Action and Restoration of Excitatory Synaptic Strength After Chronic Stress by Negative Modulators of Alpha5-Containing GABAA Receptors

“…Ketamine's therapeutic effects are induced during the brief period (~1-2 h) when it is present in the brain at sufficient concentrations to inhibit NMDARs, triggering relief of symptoms that persist for days after it is cleared from the body. During this induction phase, ketamine may preferentially reduce excitation of GABAergic inhibitory interneurons (Dwyer and Duman, 2013;Farber et al, 1998;Homayoun and Moghaddam, 2007), thereby producing a mild disinhibition of the neuronal population and increased activity in the hippocampus, entorhinal cortex, NAc, and PFC, as observed in rodents (eg, Kittelberger et al, 2012;Middleton et al, 2008;Hunt et al, 2011;Caixeta et al, 2013) and in humans (Cornwell et al, 2012;Driesen et al, 2013). This activity is accompanied by a neurochemically detectable surge of glutamate release in the PFC and NAc (Lorrain et al, 2003;Moghaddam et al, 1997;Razoux et al, 2007).…”