(The FASEB Journal. 2007;21:323.2)
© 2007 FASEB
From Clock to Clock shops: Intra- and intercellular mechanisms regulating daily timekeeping
Erik D Herzog
Biology, Washington University, Box 1137, St. Louis, MO, 63130
ABSTRACT
Biologists have long marveled at the endogenous pacemakers that dictate daily schedules in physiology and behavior. Genetics and recent advances in biological imaging and neural recording have revealed multiple "clock genes" and pacemaking cell types. In mammals, individual neurons of the suprachiasmatic nucleus (SCN) can express daily rhythms in vitro for months. To understand how SCN neurons synchronize and sustain their rhythms for coherent output, we recorded firing and clock-gene expression patterns while blocking candidate signaling pathways for at least 8 days. GABA A and B receptor antagonism increased circadian peak firing rates and rhythm precision of cultured SCN neurons, but did not impair synchrony or rhythmicity. In contrast, inhibiting Gi/o with pertussis toxin (PTX) 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 Gi/o blockade. We conclude that endogenous GABA controls the amplitude of SCN neuronal rhythms by reducing daytime firing, while Gi/o signaling suppresses nighttime firing and is necessary for synchrony among SCN neurons. We propose that VIP and G-protein signaling, not GABA, maintain and coordinate rhythms among SCN neurons.
