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

Abstract

Electroencephalogram (EEG) stands out as a highly translational tool for psychiatric research, yet rodent and human EEG are not typically obtained in the same way. In this study we developed a tool to record skull EEG in awake-behaving rats in a similar manner to how human EEG are obtained and then used this technique to test whether acute NMDA receptor antagonism alters rodent EEG signals in a similar manner as in humans. Acute MK-801 treatment elevated gamma power and reduced beta band power, which closely mirrored EEG data from healthy volunteers receiving acute ketamine. To explore the mechanisms behind these oscillatory changes, we examined the effects of GABA-A receptor blockade, finding that picrotoxin (PTX) recapitulated the decrease in sound-evoked beta oscillations observed with acute MK-801, but did not produce changes in gamma band power. Chronic treatment with either PTX or MK-801 did not affect frequency-specific oscillatory activity when tested 24 h after the last drug injection, but decreased total broadband oscillatory power. Overall, this study validated a novel platform for recording rodent EEG and demonstrated similar oscillatory changes after acute NMDA receptor antagonism in both humans and rodents, suggesting that skull EEG may be a powerful tool for further translational studies.

Increased susceptibility to pentylenetetrazol following survival of cerebral malaria in mice

“…This effect was markedly pronounced in PbA‐infected animals. Although not identical, these findings are comparable to those of Sullivan et al, who have shown a selective decrease of relative beta power in the surface EEG after systemic injection of picrotoxin, a well‐known γ‐aminobutyric acid (GABA) A receptor antagonist. In this context, present results may indicate attenuation of network inhibitory processes after CM, which eventually would make the animals more susceptible to a convulsant stimulus.…”

Alterations in High-Frequency Neuronal Oscillations in a Cynomolgus Macaque Test of Sustained Attention Following NMDA Receptor Antagonism

“…In our study, the effect on 'high' gamma following PCP administration is consistent with EEG and magnetoencephalography results reported in healthy volunteers receiving acute ketamine (Hong et al, 2010;Rivolta et al, 2015), as well as with in vivo local field potentials and EEG recordings following the administration of NMDA receptor antagonists to rodents (Ehrlichman et al, 2009;Pinault, 2008;Lazarewicz et al, 2010;Sullivan et al, 2015). The enhancement in gamma oscillations following acute NMDA receptor inhibition could result from at least two separate mechanisms in which the NMDA receptor antagonist: (i) acts directly on PV-containing GABAergic interneurons and thereby disinhibits pyramidal cells (eg, layer 5 of dlPFC); or (ii) acts directly on pyramidal cells causing a reduction in glutamate release which in turn reduces the stimulation of AMPA receptors on GABAergic interneurons which may also transiently disinhibit pyramidal cells for example in layer 3 of dlPFC (Rotaru et al, 2011;Wang et al, 2013).…”

Altered Cortical Ensembles in Mouse Models of Schizophrenia

“…While alterations in broadband spectral power at baseline have been reported in ketamine models in rodents (Kocsis et al, 2013), such increases are inconsistent across other pharmacological and genetic models of SZ (Featherstone et al, 2015; Sullivan et al, 2015), and similar observations, as well as changes in relative theta power, in SZ are present but variable (Clementz et al, 1994; Hamm et al, 2014; Hirano et al, 2015). In general, dysregulation of gamma-band dynamics and signal to noise ratio, rather than a simple increase or decrease, is a more consistent finding in SZ (Moran and Hong, 2011) and both models recapitulate this deficit in a primary sensory cortex.…”

“…While neither an acute nor a chronic ketamine model can be said to produce schizophrenia in mice, the chronic ketamine model (KET) recreates numerous schizophrenia-relevant phenotypes at multiple functional levels (Behrens et al, 2007; Phoumthipphavong et al, 2016). Indeed, in mice, chronic (7–14 days) subanesthetic ketamine not only affects NMDAR-neurotransmission, but recapitulates key SZ pathophysiology, including alterations in parvalbumin containing interneurons (Behrens et al, 2007), gamma oscillations (McNally et al, 2013; Sullivan et al, 2015), dopaminergic levels and gene expression (Chatterjee et al, 2012), dendritic spines (Phoumthipphavong et al, 2016), and cognition (Featherstone et al, 2012). …”