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GABA and Gi/o differentially control circadian rhythms and synchrony in clock neurons.

ABSTRACT: Neurons in the mammalian suprachiasmatic nuclei (SCN) generate daily rhythms in physiology and behavior, but it is unclear how they maintain and synchronize these rhythms in vivo. We hypothesized that parallel signaling pathways in the SCN are required to synchronize rhythms in these neurons for coherent output. We recorded firing and clock-gene expression patterns while blocking candidate signaling pathways for at least 8 days. GABA(A) and GABA(B) antagonism increased circadian peak firing rates and rhythm precision of cultured SCN neurons, but G(i/o) did not impair synchrony or rhythmicity. In contrast, inhibiting G(i/o) with pertussis toxin abolished rhythms in most neurons and desynchronized the population, phenocopying the loss of vasoactive intestinal polypeptide (VIP). Daily VIP receptor agonist treatment restored synchrony and rhythmicity to VIP(-/-) SCN cultures during continuous GABA receptor antagonism but not during G(i/o) blockade. Pertussis toxin did not affect circadian cycling of the liver, suggesting that G(i/o) plays a specialized role in maintaining SCN rhythmicity. We conclude that endogenous GABA controls the amplitude of SCN neuronal rhythms by reducing daytime firing, whereas G(i/o) signaling suppresses nighttime firing, and it is necessary for synchrony among SCN neurons. We propose that G(i/o), not GABA activity, converges with VIP signaling to maintain and coordinate rhythms among SCN neurons.

SUBMITTER: Aton SJ

PROVIDER: S-EPMC1748197 | biostudies-literature | 2006 Dec

REPOSITORIES: biostudies-literature

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GABA and Gi/o differentially control circadian rhythms and synchrony in clock neurons.

Aton Sara J SJ Huettner James E JE Straume Martin M Herzog Erik D ED

Proceedings of the National Academy of Sciences of the United States of America 20061130 50

Neurons in the mammalian suprachiasmatic nuclei (SCN) generate daily rhythms in physiology and behavior, but it is unclear how they maintain and synchronize these rhythms in vivo. We hypothesized that parallel signaling pathways in the SCN are required to synchronize rhythms in these neurons for coherent output. We recorded firing and clock-gene expression patterns while blocking candidate signaling pathways for at least 8 days. GABA(A) and GABA(B) antagonism increased circadian peak firing rate ...[more]

PMID: 17138670

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Project description:In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus coordinates daily rhythms including sleep-wake, hormone release, and gene expression. The cells of the SCN must synchronize to each other to drive these circadian rhythms in the rest of the body. The ontogeny of circadian cycling and intercellular coupling in the SCN remains poorly understood. Recent in vitro studies have recorded circadian rhythms from the whole embryonic SCN. Here, we tracked the onset and precision of rhythms in PERIOD2 (PER2), a clock protein, within the SCN isolated from embryonic and postnatal mice of undetermined sex. We found that a few SCN cells developed circadian periodicity in PER2 by 14.5 d after mating (E14.5) with no evidence for daily cycling on E13.5. On E15.5, the fraction of competent oscillators increased dramatically corresponding with stabilization of their circadian periods. The cells of the SCN harvested at E15.5 expressed sustained, synchronous daily rhythms. By postnatal day 2 (P2), SCN oscillators displayed the daily, dorsal-ventral phase wave in clock gene expression typical of the adult SCN. Strikingly, vasoactive intestinal polypeptide (VIP), a neuropeptide critical for synchrony in the adult SCN, and its receptor, VPAC2R, reached detectable levels after birth and after the onset of circadian synchrony. Antagonists of GABA or VIP signaling or action potentials did not disrupt circadian synchrony in the E15.5 SCN. We conclude that endogenous daily rhythms in the fetal SCN begin with few noisy oscillators on E14.5, followed by widespread oscillations that rapidly synchronize on E15.5 by an unknown mechanism.SIGNIFICANCE STATEMENT We recorded the onset of PER2 circadian oscillations during embryonic development in the mouse SCN. When isolated at E13.5, the anlagen of the SCN expresses high, arrhythmic PER2. In contrast, a few cells show noisy circadian rhythms in the isolated E14.5 SCN and most show reliable, self-sustained, synchronized rhythms in the E15.5 SCN. Strikingly, this synchrony at E15.5 appears before expression of VIP or its receptor and persists in the presence of blockers of VIP, GABA or neuronal firing. Finally, the dorsal-ventral phase wave of PER2 typical of the adult SCN appears ?P2, indicating that multiple signals may mediate circadian synchrony during the ontogeny of the SCN.

Dataset Information

GABA and Gi/o differentially control circadian rhythms and synchrony in clock neurons.

Publications

GABA and Gi/o differentially control circadian rhythms and synchrony in clock neurons.

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