GABA in the mammalian suprachiasmatic nucleus and its role in diurnal rhythmicity

Abstract

Mammals manifest circadian behaviour timed by an endogenous clock in the hypothalamic suprachiasmatic nucleus (SCN). Considerable progress has been made in identifying the molecular basis of the circadian clock, but the mechanisms by which it is translated into cyclic firing activity, high during the day and low at night, are still poorly understood. GABA (gamma-aminobutyric acid), a common inhibitory neurotransmitter in the central nervous system, is particularly densely distributed within the SCN, where it is located in the majority of neuronal somata and synaptic terminals. Using an in vitro brain-slice technique, we have now studied the effect of bath-applied GABA on adult SCN neurons at various times of the day. We find that GABA acts as an inhibitory neurotransmitter at night, decreasing the firing frequency; but during the day GABA acts as an excitatory neurotransmitter, increasing the firing frequency. We show that this dual effect, which is mediated by GABA(A) receptors, may be attributed to an oscillation in intracellular chloride concentration. A likely explanation is that the amplitude of the oscillation in firing rate, displayed by individual neurons, is amplified by the dual effect of GABA in the SCN's GABAergic network.

Morphological heterogeneity of the GABAergic network in the suprachiasmatic nucleus, the brain's circadian pacemaker

“…These authors also speculated that, depending on the firing frequency of the peptidergic neurons in which GABA is colocalised, one or another of these transmitters could be released selectively by any given terminal, which would presumably raise the possibility that GABA-containing and GABA-lacking boutons could both originate from a common peptidergic soma. However, as regards the circadian variation of GABA in the SCN, the salient point may not be the fluctuating levels of the transmitter (AnguilarRoblero et al 1993) or of its synthesising enzyme (Ramon et al 1996), but rather its bimodal excitatory\inhibitory effect on the electrical activity of its target neurons (Wagner et al 1997).…”

“…There is a strong case for the overwhelmingly intrinsic nature of the GABAergic innervation in the SCN (Jiang et al 1997 ;Strecker et al 1997 ;Wagner et al 1997), although there are also GABA-containing afferents from the intergenicular leaflet (Card & Moore, 1989) and possibly also from the surrounding hypothalamus. In long-term cultured slice explants of the SCN, a dense GABA-ir network is retained, despite the severance of virtually all extraneous inputs to the nucleus and degeneration of the severed nerve endings , which attests to the local origin of the GABA innervation.…”

“…GABA, which is responsible for much of the inhibitory neurotransmission that occurs in the brain, has been found to elicit a bimodal effect in the SCN. It excites SCN neurons during the day and inhibits them during the night, possibly due to shifts in the chloride equilibrium potential associated with GABA A receptors (Wagner et al 1997). Since virtually all SCN neurons receive local or afferent GABAergic inputs operating via GABA A receptors (Jiang et al 1997 ;Strecker et al 1997), this GABAergic network within the nucleus could serve as a substrate for synchronising and amplifying the circadian rhythm of GABA in the SCN.…”

Connexin36 vs. connexin32, “miniature” neuronal gap junctions, and limited electrotonic coupling in rodent suprachiasmatic nucleus

“…Neurons of the SCN release GABA as an inhibitory neurotransmitter [see van den Pol and Dudek (1993)], and anatomical studies have suggested that SCN neurons have local axonal projections that interconnect these neurons via GABAergic synapses (van den Pol, 1980). Electrophysiological studies using whole-cell recordings from SCN neurons in hypothalamic slices have provided evidence that action potentials in these neurons evoke GABA A -receptor-mediated postsynaptic currents in other SCN neurons (Strecker et al, 1997), and that local GABAergic circuits may contribute to synchronization of SCN neurons (Liu and Reppert, 2000;Wagner et al, 2006). However, mechanisms that could underlie GABA-mediated synchronization are not established.…”

Normal formation of the postsynaptic elements of GABAergic synapses in the reeler cerebellum

“…Recent studies revealed that GABAergic synaptic transmission also controls experience-dependent plasticity in the visual cortex [20], induces long-term potentiation, which is the electrophysiological basis of memory and learning [4,13,34,35,37,46], modulates anxiety [41,48] and generates circadian rhythms [62,65].…”