The Roles of GABAB Receptors in Cortical Network Activity

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Abstract

Temporally-structured cortical activity in the form of synchronized network oscillations and persistent activity is fundamental for cognitive processes such as sensory processing, motor control, working memory, and consolidation of long-term memory. The roles of fast glutamatergic excitation via AMPA, kainate, and NMDA receptors, as well as fast GABAergic inhibition via GABAA receptors, in such network activity have been studied in great detail. In contrast, we have only recently begun to appreciate the roles of slow inhibition via GABAB receptors in the control of cortical network activity. Here, we provide a framework for understanding the contributions of GABAB receptors in helping mediate, modulate, and moderate different types of physiological and pathological cortical network activity. We demonstrate how the slow time course of GABAB receptor-mediated inhibition is well suited to help mediate the slow oscillation, to modulate the power and spatial profile of gamma oscillations, and to moderate the relative spike timing of individual neurons during theta oscillations. We further suggest that GABAB receptors are interesting therapeutic targets in pathological conditions where cortical network activity is disturbed, such as epilepsy and schizophrenia.

Introduction

The many billions of neurons in the neocortex of the mammalian brain are heavily interconnected through chemical synapses, thereby creating a vast neuronal network. This network is arranged into many individual processing units known as microcircuits, allowing massive parallel processing of information. Microcircuits comprise sets of precisely interconnected excitatory and inhibitory neurons, and it is a fundamental challenge to understand how these microcircuits operate.

Cortical microcircuits form feedforward and feedback loops that generate spontaneous oscillatory activity, such as the slow oscillation during slow-wave sleep and the fast gamma oscillation during attention. It is likely that these oscillatory modes of network activity are fundamental to the normal function of these local microcircuits. Conversely, when these network activities are disturbed, pathology arises. Interference with the slow oscillation, for example, can lead to memory deficits and generalized epilepsy, and schizophrenia is associated with changes in gamma oscillations.

Thus, it is imperative that we study the normal synaptic function of microcircuits. To date, most studies have focused on the roles of fast excitation mediated by AMPA, kainate, and NMDA receptors and fast inhibition mediated by GABAA receptors in the control of network activity. Much less is understood about the roles of GABAB receptors. In this chapter, we will discuss recent findings that attribute a significant role of slow inhibition via GABAB receptors to the control of cortical network activity. We will first briefly review the functional properties of GABAB receptor-mediated inhibition, and then discuss its involvement in mediating, modulating, and moderating cortical network activity, before relating these functions to pathological network events.

Section snippets

Localization of GABAB Receptors

In the 1980s, a series of elegant studies by Norman Bowery (Bowery, 1993, Bowery et al., 1980, Bowery et al., 1981a, Bowery et al., 1981b, Bowery et al., 1982, Bowery et al., 1983, Wilkin et al., 1981) suggested the existence of a second GABA receptor with a distinct pharmacology from the classical GABAA receptor. This bicuculline-insensitive GABA receptor was called the GABAB receptor and was later shown to consist of a heterodimer made up of two G-protein-coupled receptor subunits, GABAB1a/b

Control of Network Activity by GABAB Receptors

The sustained synaptic activity required for GABAB receptor activation is usually met during rhythmic network activity or burst firing. This, in combination with GABAB receptor-mediated strong and long-lasting inhibitory effects, implicates GABAB receptors in the regulation of cortical network activity.

Depending on the temporal properties of network activity, GABAB receptors can (A) directly mediate slow network activity, (B) modulate the strength of fast network activity, and (C) moderate the

Conclusion

Since Norman Bowery’s seminal experiments in the 1980s, we have learned a great deal about the effect of GABAB receptor activation at the cellular level. However, the functional role of GABAB receptors at the network level is only just starting to emerge. Here, we have outlined a framework for understanding the contributions of GABAB receptors in helping to mediate, modulate, and moderate different types of physiological and pathological cortical network activity. We have reviewed how GABAB

Abbreviations

    AMPA

    α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

    GABA

    γ-aminobutyric acid

    IPSP

    inhibitory postsynaptic potential

    NMDA

    N-methyl-D-aspartate

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