Membrane Currents, Gene Expression, and Circadian Clocks

Abstract

Neuronal circadian oscillators in the mammalian and Drosophila brain express a circadian clock comprised of interlocking gene transcription feedback loops. The genetic clock regulates the membrane electrical activity by poorly understood signaling pathways to generate a circadian pattern of action potential firing. During the day, Na þ channels contribute an excitatory drive for the spontaneous activity of circadian clock neurons. Multiple types of K þ channels regulate the action potential firing pattern and the nightly reduction in neuronal activity. The membrane electrical activity possibly signaling by changes in intracellular Ca 2þ and cyclic adenosine monophosphate (cAMP) regulates the activity of the gene clock. A decline in the signaling pathways that link the gene clock and neural activity during aging and disease may weaken the circadian output and generate significant impacts on human health. N eurons in the suprachiasmatic nucleus (SCN) function as part of a central timing circuit that drives daily changes in our behavior and underlying physiology. A hallmark feature of SCN neurons is that they are electrically silent during the night, start firing action potentials near dawn, and then continue to generate action potentials with a slow and steady pace all day long. These rhythms in electrical activity are critical for the function of the circadian timing system. This article reviews what is known about the ionic and molecular mechanisms driving the rhythmic firing patterns in our body's clock. We raise the hypothesis that a decline in neural activity in the central clock may be a critical mechanism by which aging and disease may weaken the circadian output and contribute to a set of symptoms that impacts human health. THE IONIC MECHANISMS UNDERLYING NEURAL ACTIVITY RHYTHMSSCN neurons generate action potentials in the absence of synaptic drive, and can therefore be considered endogenously active neurons.

Regulating the Suprachiasmatic Nucleus (SCN) Circadian Clockwork: Interplay between Cell-Autonomous and Circuit-Level Mechanisms

“…One likely avenue is via increases in intracellular calcium levels ([Ca 2þ ] i ) because of the opening of voltage-gated calcium channels and release from intracellular stores (see Allen et al 2016). Consistent with this, fluorescent imaging using a genetically encoded calcium reporter has revealed a pronounced circadian cycle of [Ca 2þ ] i in SCN neurons that peaks at CT06, coincident with high firing rates and increasing Per expression, as revealed by simultaneous bioluminescent imaging (Brancaccio et al 2013).…”

“…Although NALCN channels are critical in regulating daytime firing properties, the hyperpolarized resting membrane potential and decreased input resistance observed at night in mouse SCN neurons suggests that the overall change in K þ conductance is primarily driving the daily oscillations of electrical activity. Studies focused on identifying specific ionic conductances that are regulated by the molecular clock to dictate daytime and/or nighttime firing properties in clock neurons are considered further in Allen et al (2016). Thus, daily oscillations in K þ and Na þ conductances enable clock neurons to convert their TTFL into circadian rhythms in output.…”

The circadian clock: a tale of genetic–electrical interplay and synaptic integration

“…This current is driven by the rhythmic expression of NCA Localization Factor -1, providing an example of signaling pathway linking the molecular clock to ion channel function [9]. This channel pathway is a new addition to the families of cation channels that provide depolarizing forces to SCN neurons during the day, elevating their resting membrane potential and increasing firing rate [10–12]. The L-type calcium channel is another key cation channel involved in sustaining excitation in SCN neurons [1,8].…”

“…This provides yet another example of a pathway where the TTFL can influence ion channel activity. Some potassium channels may reduce their conductivity to support such depolarization during the day [10–12]. For example, a reduction in the activity of the small-conductance calcium-activated potassium channels transits a proportion of daytime SCN neurons into hyperexcitation and depolarization blockade states, where they ceased firing [1,14].…”

“…In the evening, the activity of a number of potassium currents peaks to hyperpolarize and silence clock neurons [10–12]. Reduction of Per1 activity by antisense oligonucleotides suppressed firing of SCN neurons by reducing intracellular calcium levels and the conductance of the large calcium-activated potassium currents (BK; [15]).…”