Cortical high gamma network oscillations and connectivity: a translational index for antipsychotics to normalize aberrant neurophysiological activity

A Ahnaou,T Van De Casteele,W H I M Drinkenburg,H Huysmans

doi:10.1038/s41398-017-0002-9

Abstract

Oscillatory activity in the gamma frequency range is a critical mechanism, which integrates neural networks within and across brain structures during cognitive processes. In schizophrenia, abnormalities in high gamma oscillations are ubiquitous and most likely reflect dysfunction in neuronal networks. In conscious rats, disturbed network oscillations associated with positive symptoms and cognitive deficits were modeled in different cortical areas by the dopaminergic agonist (amphetamine) and the N-methyl-D-aspartate (NMDA) receptor antagonists (PCP and MK801). Subsequently, the efficacies of marketed atypical antipsychotics (olanzapine, risperidone, and clozapine) to normalize dysfunctional oscillations and network connectivity were examined. Acute NMDA antagonists elicited aberrant synchrony in the gamma frequency oscillations. In addition, coherent slow alpha network activity was observed with MK801 and amphetamine, both of whose oscillatory rhythms were correlated with pronounced locomotor activity. All antipsychotics commonly decreased slow alpha and high gamma network oscillations in different cortical regions as well as motion behavior. In the combined treatments, antipsychotics attenuated NMDA antagonist-induced abnormalities in functional network oscillations and connectivity, whose effects on motor behavior is mechanistically related. These results suggest that pharmacologically induced disruption of cortical gamma oscillations and network connectivity in rats is a candidate model to study dysfunctional oscillatory patterns described in positive and negative symptoms of schizophrenia. The efficacy of antipsychotics to rescue cortical network oscillatory patterns is in line with the idea that glutamatergic and dopaminergic systems play a role in maintaining the integrity of cortical circuits. Thus, gamma oscillations could provide a powerful translational index to assess the integrity of neural networks and to evaluate the efficacy of drugs with potential antipsychotic properties.

Highlights

Ongoing brain oscillations determine the dynamic changes in brain states, and influence alertness such as cortical computations, cognitive perceptual grouping, attention-dependent stimulus selection, subsystem integration, working memory, and consciousness[1,2,3,4,5,6,7,8,9,10]
The NMDA antagonists and the dopaminergic agonist were used to model the aberrant cortical network oscillations in rats that resemble the dysfunctional network oscillations widely described in schizophrenia
In the present studies, (1) all NMDA receptor antagonists elicited aberrant network oscillations in the higher gamma frequency range associated with pronounced hyperactivity, while a consistent abnormal slow alpha coherent oscillatory activity was observed with both amphetamine and MK801, (2) all antipsychotics decreased EEG slow alpha and higher network gamma oscillations as well as decreased motion levels, (3) pretreatment with antipsychotics attenuated drug challengeinduced abnormal slow alpha and higher gamma network synchrony, which was mechanism-dependent

Summary

Introduction

Ongoing brain oscillations determine the dynamic changes in brain states, and influence alertness such as cortical computations, cognitive perceptual grouping, attention-dependent stimulus selection, subsystem integration, working memory, and consciousness[1,2,3,4,5,6,7,8,9,10]. PV interneurons are Ahnaou et al Translational Psychiatry (2017)7:1285 crucial in the genesis of gamma oscillations in cortical circuits, as they exert powerful, precisely timed recurrent inhibition onto their target pyramidal cells and inhibitory interneurons[16,23,24]. These GABAergic interneurons appear to be under the control of glutamatergic system, which is known to be abnormal in schizophrenia[18,25,26,27,28,29]

Methods

Results

Conclusion