Abstract
In mammals, the circadian rhythms are regulated by the central clock located in the hypothalamic suprachiasmatic nucleus (SCN), which is composed of heterogeneous neurons with various neurotransmitters. Among them an inhibitory neurotransmitter, γ-Amino-Butyric-Acid (GABA), is expressed in almost all SCN neurons, however, its role in the circadian physiology is still unclear. Here, we show that the SCN of fetal mice lacking vesicular GABA transporter (VGAT−/−) or GABA synthesizing enzyme, glutamate decarboxylase (GAD65−/−/67−/−), shows burst firings associated with large Ca2+ spikes throughout 24 hours, which spread over the entire SCN slice in synchrony. By contrast, circadian PER2 rhythms in VGAT−/− and GAD65−/−/67−/− SCN remain intact. SCN-specific VGAT deletion in adult mice dampens circadian behavior rhythm. These findings indicate that GABA in the fetal SCN is necessary for refinement of the circadian firing rhythm and, possibly, for stabilizing the output signals, but not for circadian integration of multiple cellular oscillations.
Highlights
In mammals, the circadian rhythms are regulated by the central clock located in the hypothalamic suprachiasmatic nucleus (SCN), which is composed of heterogeneous neurons with various neurotransmitters
We examined the effect of GABA deficiency on the circadian rhythms of spontaneous firing, intracellular Ca2+ level, and circadian PER2 rhythm in the fetal SCN cultured on multielectrode array dish (MED)
Since the vesicular GABA transporter (VGAT)−/− mice do not survive after birth[31], we obtained VGAT−/− SCN slices at the embryonic day 19 or 20 together with the wild type (WT) and VGAT+/− littermates from VGAT+/− females crossed with VGAT+/− males
Summary
The circadian rhythms are regulated by the central clock located in the hypothalamic suprachiasmatic nucleus (SCN), which is composed of heterogeneous neurons with various neurotransmitters. SCN-specific VGAT deletion in adult mice dampens circadian behavior rhythm These findings indicate that GABA in the fetal SCN is necessary for refinement of the circadian firing rhythm and, possibly, for stabilizing the output signals, but not for circadian integration of multiple cellular oscillations. 16% in the dispersed SCN cell culture of neonatal rats, indicating that GABA action is primarily inhibitory but excitatory in some neurons[12]. These controversies are due in part to differences in pharmacological tools and measuring approaches. In the dispersed SCN cell culture of neonatal rats, circadian rhythms were synchronized in neuron pairs with functional synaptic communications and were not detected in any of the pairs lacking synaptic communication[12]. The firing rate of spontaneous discharge in the cultured SCN on the multielectrode array dish (MED) ranged typically from 0–1 Hz at the subjective night to 6–10 Hz at the subjective day[6,26]
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