Circadian rhythms are biological oscillations with a period of about 24 hours. These rhythms are maintained by an innate genetically determined time-keeping system called the circadian clock. A large number of the proteins involved in the regulation of this clock are transcription factors controlling rhythmic transcription of
Most light-sensitive organisms have built-in time-measuring devices that are commonly known as circadian clocks. The term
The intracellular circadian clock is based on a transcription-translation feedback system that drive the self-sustaining clock mechanism in the suprachiasmatic nucleus (SCN, the “master clock”) and in peripheral tissues (“peripheral clocks”) [
In mammals, the SCN synchronizes multiple peripheral clocks, in numerous tissues and cell types, presumably via the combination of neural and humoral signaling [
Glial cells make up a large fraction of human nervous system cells, with numbers exceeding those of neurons by a factor of ten, depending on the brain structure studied. Particularly, glial cells occupy about half the volume of the brain and participate in diverse functions, including regulation of synaptic transmission, plasticity, behavior, and synapse development, and these cells are also involved in neurodegeneration [
This type of glial cell is involved in the buffering of extracellular K+, regulating neurotransmitter release [
In 1990, it was suggested that glial cells might express molecular oscillators, which are based on the clock protein PER. Particularly, it was demonstrated that PER was localized both in neurons and glial cells of the fly brain, which showed robust circadian rhythms and abundance [
Several studies have explored the role of the mammalian PER-based oscillator in glial physiology. It has been reported that
Concerning Glu, it is known that this neurotransmitter participates in photic entrainment of circadian rhythms. In 2015, it was reported that in cultured Bergmann glial cells, BMAL1 expression is Glu time- and dose-dependent. This phenomena might be a result of stabilization of the protein after it has been phosphorylated by PKA (cyclic AMP-dependent protein kinase) and/or PKC (Ca2+/diacylglycerol-dependent protein kinase), pointing out that Glu is critically involved in glial BMAL1 expression and that glial cells are important in the control of circadian rhythms in the cerebellum [
It has been recently demonstrated that not only SCN neurons but also SCN astrocytes possess pacemaking properties [
Moreover, it was reported that SCN astrocytes are functional circadian oscillators, which modulate the period of SCN and the rest-activity rhythms [
Earlier studies in SCN astrocytes revealed high-amplitude daily rhythms in the expression of GFAP [
A daily variation of GFAP in the mouse SCN, as well as the NF-
ROR
Furthermore, it has also been reported that
Other nuclear receptors involved in the inflammatory response are REV-ERB
Circadian expression of clock genes such as
Gliotransmission is the process by which astrocytes communicate with immediate glia and neurons through the release of transmitters such as ATP and Glu [
Mammalian and insect glial cells modulate circadian neuronal circuitry and behavior via glial calcium signaling [
Recently, Xu and colleagues reported the existence of canonical circadian clock genes in mammalian retinal Müller glia. This study not only demonstrated that retinal Müller cells generate molecular circadian rhythms isolated from other retinal cell types but also demonstrated that these retinal cells exhibit unique features of their molecular circadian clock compared to the retina as a complex system. However, it is important to highlight that the authors mention that both mouse and human Müller cells exhibit species-specific differences in the gene dependence of their clocks [
These glial cells are the main innate immune cells of the CNS and play essential functions in the maintenance of neuronal circuitry, regulation of behavior, and functional state of neurotransmission [
Knowledge about a molecular clock in this type of glial cells is relatively recent. In 2011, it was demonstrated that the clock genes are constitutively expressed in both cultured murine microglia and the microglial cell line BV-2 cells. In the same study, it was also reported that ATP selectively promotes the expression of mRNA and corresponding protein for
In 2015, Fonken and coworkers reported that microglia possesses circadian clock mechanisms and displays rhythmic fluctuations in both basal inflammatory gene expression and inflammatory potential. It is interesting to note that inflammatory potential in microglia is associated with time-of-day differences, this is because of the circadian differences observed in sickness response [
Recently, Nakazato and colleagues demonstrated that
These cells are the myelinating glia of the CNS, provide axonal metabolic support [
Recent studies indicate that defective clock genes in glial cells participate in diverse brain pathologies, mainly in psychiatric diseases. However, it is important to keep in mind that a single clock gene can have different repercussions on health and that several clock genes may be related to the same pathology (for detailed review, see reference [
Moreover, alterations in
Nowadays, disturbances in the sleep parameters are common. These disturbances are associated with a spectrum of neurological and psychiatric disorders. Interestingly, clock genes are also involved in variations related with sleep time, sleep fragmentation, and atypical responses following sleep deprivation [
Additionally, it has been shown that
Finally, abnormal microglial cells are also associated with neurological disorders [
The expression of clock genes in glial cells has great importance for the maintenance of a healthy brain (Table
Circadian functions regulated by the glial cells.
CG/CCG/molecule | Circadian functions | References |
---|---|---|
|
||
|
Regulation of the glutamatergic system ( |
[ |
Modulates ATP release | [ | |
|
Regulation of the glutamatergic system ( |
[ |
|
Regulation of nociceptive processes | [ |
Modulates ATP release | [ | |
|
Regulation of the glutamatergic system (GLAST protein levels) | [ |
Regulation of nociceptive processes | [ | |
Modulates ATP release | [ | |
Regulates to |
[ | |
|
Modulates the period of the SCN and behavior | [ |
Regulation of nociceptive processes | [ | |
|
Regulation of nociceptive processes | [ |
|
Participates in metabolic exchanges and plasticity | [ |
NF- |
SCN astrocytes mediate the immune signals to the circadian system via NF- |
[ |
|
Participates in the regulation of the inflammatory response (inhibits NF- |
[ |
|
Participates in the regulation of the inflammatory response (both isoforms inhibit TNF-induced upregulation of |
[ |
|
Regulation of the glutamatergic system (glutamate-glutamine metabolic cycle) | [ |
Regulation of various spinal sensory functions | [ | |
|
Regulation of various spinal sensory functions | [ |
IP3 | Modulates ATP release (IP3-dependent calcium signaling) | [ |
ATP | Regulation of the energy metabolism and glial activity | [ |
Ca2+ | Modulation of circadian behavior | [ |
Regulates the release of gliotransmitters | [ | |
Glu | Regulates BMAL1 expression (Glu time- and dose-dependent) | [ |
Provides the inhibitory astrocytic-neuronal coupling signal during nighttime in the SCN via NMDAR2C | [ | |
|
||
|
||
ATP | Upregulates the |
[ |
CatS | Regulates the synaptic strength, including neuronal transmission and spine density via the proteolytic modification of the perineuronal environment | [ |
|
Implicated in the inflammatory response (modulates |
[ |
|
||
|
||
|
Regulation of the OPC proliferation | [ |
ATP: adenosine triphosphate;
The authors declare no competing financial interests.
Donají Chi-Castañeda is supported by SNI-CONACYT, and the work in the lab (Arturo Ortega) is supported by CONACYT-México (255087) and “