Elsevier

Frontiers in Neuroendocrinology

Volume 44, January 2017, Pages 35-82
Frontiers in Neuroendocrinology

Review article
The dynamics of GABA signaling: Revelations from the circadian pacemaker in the suprachiasmatic nucleus

https://doi.org/10.1016/j.yfrne.2016.11.003Get rights and content

Highlights

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    Synaptic and non-synaptic release of GABA occurs in the suprachiasmatic nucleus.

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    GABAA-PHASIC and GABAA-TONIC receptors are active in the suprachiasmatic nucleus.

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    GABA has inhibitory and excitatory actions on suprachiasmatic neurons.

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    GABAA and GABAB receptors modulate the phase of the circadian pacemaker.

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    GABA can both inhibit and mediate the effects of light on the circadian pacemaker.

Abstract

Virtually every neuron within the suprachiasmatic nucleus (SCN) communicates via GABAergic signaling. The extracellular levels of GABA within the SCN are determined by a complex interaction of synthesis and transport, as well as synaptic and non-synaptic release. The response to GABA is mediated by GABAA receptors that respond to both phasic and tonic GABA release and that can produce excitatory as well as inhibitory cellular responses. GABA also influences circadian control through the exclusively inhibitory effects of GABAB receptors. Both GABA and neuropeptide signaling occur within the SCN, although the functional consequences of the interactions of these signals are not well understood. This review considers the role of GABA in the circadian pacemaker, in the mechanisms responsible for the generation of circadian rhythms, in the ability of non-photic stimuli to reset the phase of the pacemaker, and in the ability of the day-night cycle to entrain the pacemaker.

Section snippets

The SCN: a primary circadian pacemaker

The SCN has been identified as the location of a circadian pacemaker that generates endogenous rhythmicity and mediates the entrainment of that rhythmicity with the day-night cycle in mammals, including humans (Moore and Eichler, 1972, Stephan and Zucker, 1972, Cohen and Albers, 1991). Remarkable progress has been made over the last few decades in defining the molecular mechanisms that generate circadian rhythmicity (for recent reviews see Hastings et al., 2014, Zhang and Kay, 2010). In brief,

Investigation of GABA function within the SCN

GABA is recognized as the primary inhibitory neurotransmitter in the brain. While much has been learned about GABA’s actions, the study of GABA function has been complicated by its role in so many different circuits and the complexity in so many features of its signaling. The SCN provides an outstanding model system to study the dynamics of GABA signaling because GABA is found in such a large percentage of SCN neurons and, as a circadian pacemaker, the SCN provides a GABAergic network with

GABA release and its interaction with other neurochemical signals

It is now clear that many neurons, including GABAergic neurons, can release more than one neurochemical signal. Based on the frequency with which neurochemical signals are co-expressed in the brain, it seems likely that co-release is a common phenomenon, although actual demonstrations of co-release from neurons are rare. There is evidence, however, that GABA can be released with other low molecular weight neurotransmitters such as glycine and glutamate (Tritsch et al., 2016). There is also

GABA receptors

Receptors that bind GABA are found on most neurons in the mammalian brain (Decavel and van den Pol, 1990, Mody and Pearce, 2004). The effects of GABA are mediated by two major classes of GABA receptors: GABAA and GABAB (Olsen and Sieghart, 2008, Olsen and Sieghart, 2009, Benarroch, 2012, Ulrich and Bettler, 2007), both of which are found in the SCN (Table 1) (Francois-Bellan et al., 1989b). GABAA receptors are ligand-gated chloride (Cl−) ion channels and GABAB receptors are metabotropic

Factors regulating extracellular levels of GABA

The amount and distribution of GABA in the intra- and extracellular space depends on a complex interaction among factors controlling GABA release, synthesis, and transport. As discussed above (Section 3), GABA release from neurons depends on the exocytosis of GABA containing vesicles resulting from Ca2+ influx via voltage-gated ion channels or Ca2+ released from intracellular stores. Of course, the amount of GABA release from neurons depends on the amount of GABA contained within vesicles that

Excitatory and inhibitory effects of GABA: role of cation Cl− cotransporters (CCCs)

While GABA is widely recognized as the primary inhibitory neurotransmitter in the adult brain, GABA acts primarily as an excitatory neurotransmitter during early development (for a review see Ben Ari et al., 2012). The transition from GABA’s depolarizing effects to its hyperpolarizing effects appears to occur around the second postnatal week in rodents (Owens and Kriegstein, 2002, Kilb, 2012). Studies in the SCN are consistent with this timeframe, in that GABA primarily elevates intracellular Ca

Cellular responses to GABA within the SCN

Studies of the cellular actions of GABA have examined the response of SCN neurons to GABA as well as to selective GABAA- and GABAB-active drugs (Table 3, Table 4, Table 5). The results of these studies are complex, and as yet no clear consensus of the cellular actions of GABA within the SCN has been reached. At least some of the differences in the results among studies may be due to the use of different techniques to administer GABA as well as differences in the methods used to record the

Role of GABA in the coupling of circadian clock cells into a circadian pacemaker in the SCN

Cells in the SCN exhibit a synchronized circadian rhythm in spontaneous neural activity in vivo (Inouye and Kawamura, 1979). Although individual SCN neurons can retain the ability to generate rhythms of around 24 h even when isolated in culture, these neurons are out of phase with each other and display circadian periods ranging from 20 to 28 h (Welsh et al., 1995, Honma et al., 1998, Herzog et al., 1998). SCN clock cells do not appear to be a specialized or an anatomically localized class of

Role of GABA in entrainment of the circadian pacemaker

Entrainment is the process whereby an endogenous circadian pacemaker is synchronized to an external rhythm (e.g., the LD cycle) so that the endogenous pacemaker adopts the period length of the external rhythm. Photic entrainment of the SCN requires a series of neurochemical events that transduce light into a signal that can ultimately phase shift the pacemaker. Both acute and sustained activation of GABA receptors in the SCN are involved in mediating the effects of photic stimuli on circadian

GABA as an SCN output signal

How efferent signals of the SCN impart circadian rhythmicity to the large number of physiological systems controlled by the circadian timing system is not known. It is clear, however, that understanding the efferent system of the SCN requires consideration of the properties of its target tissues. Different models of the organization of the mammalian circadian timing system have been discussed for more than 40 years (Moore-Ede et al., 1976). The possibilities range from a single master circadian

Modulation of GABA neurotransmission

A variety of substances other than endogenous GABA can act on GABA receptors. Indeed, GABA-active drugs are used extensively for therapeutic purposes ranging from the treatment of psychiatric disease to sleep disorders. The extent to which these therapeutic actions occur at the level of the SCN is not known. It is clear, however, that disruptions of the circadian timing system have major health consequences (Zelinski et al., 2014, Baron and Reid, 2014). Not only does modulation of GABA

Conclusions

Despite substantial progress in understanding the role of GABA in circadian timing, fundamental questions about GABA neurotransmission within the SCN remain unanswered. Although anatomical evidence indicates that GABA is frequently colocalized with multiple neuropeptides (e.g. VIP and GRP) we know very little about the functional consequences of their corelease. Only a few studies have examined the circadian effects of the interaction of multiple signals in the SCN (Albers et al., 1991, Peters

Acknowledgements

The original research discussed in this paper was supported by NIH grants GM31199, GM34798, NS30022, NS34586, MH58789, NS0780220, MH067420, MH12956, MH12683, NS09927 and ONR N00014-87-K0172 to HEA; NIH grant NS092545 to JCW; NIH grants NS082413, NS051183, GM086683, GM086683 and NS084683 to KLG; and NSF grant IOS-1022050 to DLH. The authors thank Drs. Charles Allen, Chistopher Colwell, Ralph Mistleberger, and Martin Moore-Ede for permission to adapt figures. The authors also thank Drs. Jennifer

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