γ-Aminobutyric acid receptor type a receptor potentiation reduces firing of neuronal assemblies in a computational cortical model

Abstract

Background: The understanding of how general anesthetics act on individual cells and on global brain function has increased significantly during the last decade. What remains poorly understood is how anesthetics act at intermediate scales. Several major theories emphasize the importance of neuronal groups, sets of strongly connected neurons that fire in a time-locked fashion, in all aspects of brain function, particularly as a necessary substrate of consciousness. The authors have undertaken computer modeling to determine how ã-aminobutyric acid receptor type A (GABAA) receptor potentiating agents such as propofol may influence the dynamics of neuronal group formation and ongoing activity. Methods: A computer model of a cortical network with connections modified by synaptic plasticity was examined. At baseline, the model spontaneously formed neuronal groups. Direct effects of GABAA receptor potentiation and indirect effects on input drive were then examined to study their effects on this process. Results: Potentiation of GABAA inhibition and input drive reduction reduced the firing frequency of inhibitory and excitatory neurons in a dose-dependent manner. The diminution in spiking rates led to dramatic reductions in the firing frequency of neuronal groups. Simulated electroencephalographic output from the model at baseline exhibits gamma and theta rhythmicity. The direct and indirect GABA A effects reduce the amplitude of these underlying rhythms and modestly slow the gamma rhythm. Conclusions: GABAA facilitation both directly and indirectly inhibits the ability of neurons to form groups spontaneously. A lack of group formation is consistent with some theories of anesthetic-induced loss of memory formation and consciousness. Copyright © 2012, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins.