Abstract
Abnormalities in EEG gamma band oscillations (GBO, 30–80 Hz) serve as a prominent biomarker of schizophrenia (Sz), associated with positive, negative, and cognitive symptoms. Chronic, subanesthetic administration of antagonists of N-methyl-D-aspartate receptors (NMDAR), such as ketamine, elicits behavioral effects, and alterations in cortical interneurons similar to those observed in Sz. However, the chronic effects of ketamine on neocortical GBO are unknown. Thus, here we examine the effects of chronic (five daily i.p. injections) application of ketamine (5 and 30 mg/kg) and the more specific NMDAR antagonist, MK-801 (0.02, 0.5, and 2 mg/kg), on neocortical GBO ex vivo. Oscillations were generated by focal application of the glutamate receptor agonist, kainate (KA), in coronal brain slices containing the prelimbic cortex. This region constitutes the rodent analog of the human dorsolateral prefrontal cortex, a brain region strongly implicated in Sz-pathophysiology. Here we report the novel finding that chronic ketamine elicits a reduction in the peak oscillatory frequency of KA-elicited oscillations (from 47 to 40 Hz at 30 mg/kg). Moreover, the power of GBO in the 40–50 Hz band was reduced. These findings are reminiscent of both the reduced resonance frequency and power of cortical oscillations observed in Sz clinical studies. Surprisingly, MK-801 had no significant effect, suggesting care is needed when equating Sz-like behavioral effects elicited by different NMDAR antagonists to alterations in GBO activity. We conclude that chronic ketamine in the mouse mimics GBO abnormalities observed in Sz patients. Use of this ex vivo slice model may be useful in testing therapeutic compounds which rescue these GBO abnormalities.
Highlights
Mounting evidence suggests that the symptoms of neuropsychiatric disorders, such as schizophrenia (Sz), arise from a failure of the brain to properly integrate activity across local and distributed neuronal circuitry [1,2,3]
The results reported in this study represent the first investigation of the effects of chronic (5 days) application of N -methyl-d-aspartate receptor (NMDAR) antagonists, ketamine, and MK-801, on gamma band oscillations (GBO) in the adult mouse neocortex, ex vivo
There were three main findings: [1] Administration of chronic subanesthetic ketamine at 30 and 5 mg/kg reduced the peak frequency of the elicited oscillations; [2] Chronic ketamine at 30 mg/kg reduced the power of cortical GBO within the 40–50 Hz band; [3] Somewhat surprisingly, the effect of ketamine was not mimicked by a more selective NMDAR antagonist, MK-801
Summary
Mounting evidence suggests that the symptoms of neuropsychiatric disorders, such as schizophrenia (Sz), arise from a failure of the brain to properly integrate activity across local and distributed neuronal circuitry [1,2,3]. Over the last few decades, administration of psychotomimetic agents, such as the N -methyl-d-aspartate receptor (NMDAR) antagonist, ketamine, have provided the most reliable and widely used means to mimic Sz-like symptoms, and currently represents the “gold-standard” for modeling this disorder in both humans, and animals [8,9,10]. Recent in vivo rodent studies have shown that acute systemic administration of NMDAR antagonists leads to a significant potentiation of spontaneous GBO activity in frontal cortex [11,12,13]. Such findings have been largely confirmed ex vivo by our lab and others [14, 15]. GBO were elicited in submerged neocortical slices using our established method [15] utilizing brief, focal application of the glutamate receptor agonist kainate (KA)
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