Linking neural activity and molecular oscillations in the SCN

Abstract

Neurons in the suprachiasmatic nucleus (SCN) function as part of a central timing circuit that drives daily changes in our behaviour and underlying physiology. A hallmark feature of SCN neuronal populations is that they are mostly electrically silent during the night, start to fire action potentials near dawn and then continue to generate action potentials with a slow and steady pace all day long. Sets of currents are responsible for this daily rhythm, with the strongest evidence for persistent Na+ currents, L-type Ca2+ currents, hyperpolarization-activated currents (IH), large-conductance Ca2+ activated K+ (BK) currents and fast delayed rectifier (FDR) K+ currents. These rhythms in electrical activity are crucial for the function of the circadian timing system, including the expression of clock genes, and decline with ageing and disease. This article reviews our current understanding of the ionic and molecular mechanisms that drive the rhythmic firing patterns in the SCN.

Genetic activation of BK currents in vivo generates bidirectional effects on neuronal excitability

“…During the day, I DR activation may preclude fast-activating BK currents from increasing firing, as has been proposed in cerebellar and vestibular neurons (28,35). The L-type component of the voltage-gated Ca 2+ current is also larger during the day in SCN neurons (30), potentially affecting activation of both BK and other Ca 2+ -activated currents such as SK. However, because our SCN BK currents were recorded under conditions where the Ca 2+ influx can vary (SI Materials and Methods), the lack of a daytime left shift in the BK current-voltage relationship from WT or Tg-BK R207Q neurons (Fig.…”

“…When taken together, these data show that Tg-BK R207Q neurons had BK currents that were fastactivating with similar current magnitudes and voltage dependence during the night and day. This fortuitous result allowed us to focus our analysis on the impact of similar BK currents in Tg-BK R207Q neurons under distinct night and day membrane environments, because SCN neurons undergo circadian regulation of other ionic currents (30).…”

“…S1C), although whether the day and night BK current deactivation rates differ in Tg-BK R207Q neurons is not known. In addition, several other SCN currents are known to undergo circadian regulation (30). Most notably, I DR is smallest at night (30), when firing in Tg-BK R207Q neurons is increased compared with WT.…”

“…In addition, several other SCN currents are known to undergo circadian regulation (30). Most notably, I DR is smallest at night (30), when firing in Tg-BK R207Q neurons is increased compared with WT. During the day, I DR activation may preclude fast-activating BK currents from increasing firing, as has been proposed in cerebellar and vestibular neurons (28,35).…”

“…One type of neuron amenable to this question is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, the brain's intrinsic "clock." SCN neurons exhibit daily alterations in ionic currents that drive circadian oscillations in action potential activity (29,30), providing a unique state-dependent context to study the impact of enhanced BK currents. Therefore, we sought to examine whether inducing BK currents with fast-activating properties would produce different neuronal excitability phenotypes under the distinct ionic contexts of day and night SCN neurons.…”