Receptor Density Affects Circadian Rhythms in the Biological Clock

Researchers at Washington University in St. Louis are delving into the mechanisms of the human biological clock and how it keeps time. Their latest findings, published on July 24 in the Proceedings of the National Academy of Sciences, shed light on longstanding questions about the generation and maintenance of circadian rhythms.

In animals, signals from a central brain clock generate seasonal and daily rhythms. These signals help the body prepare for expected environmental changes, optimizing sleep, diet, and daily activities. In mammals, circadian signals originate from a small region in the brain called the suprachiasmatic nucleus (SCN). Previous studies by Washington University and other institutions have tried to determine if the neurotransmitter GABA plays a role in synchronizing circadian rhythms among individual SCN neurons. However, GABA's function in the SCN remains unclear.
"In the past, we've published data on blocking the GABA system and found only modest increases in synchrony among SCN cells," said Daniel Granados-Fuentes, the first author of the new study. Consequently, Granados-Fuentes and his team adopted a different approach. The researchers modified the expression of two GABA receptors to assess whether receptor density impacts synchrony or behavior.

Granados-Fuentes explained, "Regulating the number of receptors is considered important for physiological processes like learning and memory, but not for circadian rhythms." However, in this case, altering the density of γ-2 or δ GABA receptors had significant effects. Reducing these receptors in mutant mice lowered the amplitude of their circadian rhythms to one-third. The mice also increased their daytime running and decreased nighttime running.

The researchers found that reducing or mutating γ-2 or δ GABA receptors halved the synchrony and amplitude of circadian SCN cells' measurements in vitro. Overexpression of either GABA receptor could compensate for the absence of the other, suggesting that both receptors might function similarly in the SCN despite mediating different physiological processes.
These findings advance our understanding of the SCN and highlight the crucial role of GABA receptor density in regulating circadian rhythms. This research provides a foundation for future studies that could explore therapeutic strategies for circadian rhythm disorders.