The Roles of GABAB Receptors in Cortical Network Activity
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
References (145)
- et al.
Hetero-oligomerization between GABAA and GABAB receptors regulates GABAB receptor trafficking
Journal of Biological Chemistry
(2004) The physiology and pharmacology of hippocampal formation theta rhythms
Progress in Neurobiology
(1986)- et al.
Structure/activity studies at a baclofen-sensitive, bicuculline-insensitive GABA receptor
Advances in Biochemical Psychopharmacology
(1981) - et al.
Characteristics of GABAB receptor binding sites on rat whole brain synaptic membranes
British Journal of Pharmacology
(1983) - et al.
What determines the frequency of fast network oscillations with irregular neural discharges? I. Synaptic dynamics and excitation-inhibition balance
Journal of Neurophysiology
(2003) - et al.
Driving fast-spiking cells induces gamma rhythm and controls sensory responses
Nature
(2009) - et al.
Oscillatory coupling of hippocampal pyramidal cells and interneurons in the behaving rat
Journal of Neuroscience
(1999) - et al.
Coexistence of gamma and high-frequency oscillations in rat medial entorhinal cortex in vitro
Journal of Physiology
(2004) - et al.
The memory function of sleep
Nature Reviews Neuroscience
(2010) - et al.
Distinct roles for the kainate receptor subunits GluR5 and GluR6 in kainate-induced hippocampal gamma oscillations
Journal of Neuroscience
(2004)