Beyond their recognized role in synapse development and neurodegeneration, astrocytes provide a delicate ensheathment of synapses in the mature brain (Chao et al., 2002; Theodosis et al., 2008). It is well-established that the degree of astrocytic ensheathing greatly changes with the brain area, hinting local specialization. In the hippocampus for example, a single astrocyte is in close proximity to few hundreds dendrites of different neurons, but can ensheathe up to several hundred thousands synapses (Bushong et al., 2002; Halassa et al., 2007; Agulhon et al., 2008). Such morphological arrangement provides the structural substrate for tight functional interactions between astrocytes and neurons (Saab et al., 2012; Bernardinelli et al., 2014).

Astrocytes are also recognized for their role in clearance of neurotransmitters, such as Glu and gamma-aminobutyric acid (GABA), from the synaptic cleft. Perisynaptic astrocytes processes are indeed enriched in transporters that guarantee rapid and efficient removal of the released neurotransmitters (Anderson and Swanson, 2000; Conti et al., 2004). Interestingly, the regulation of the kinetics and the extent of neurotransmitter clearance by astrocytes have been related to synaptic plasticity insofar as they both affect the degree of postsynaptic activation and desensitization (Tzingounis and Wadiche, 2007). Moreover, through the release of a variety of neuroactive molecules, such as Glu, D-serine, adenosine triphosphate (ATP), adenosine, GABA, tumor necrosis factor-α (TNFα), prostaglandins, proteins and peptides, astrocytes are capable of regulating synaptic transmission and plasticity (Halassa and Haydon, 2010; Araque et al., 2014). These neuroactive molecules activate extrasynaptic metabotropic and ionotropic receptors, modifying neurotransmitter release and regulating short-term plasticity and synaptic efficacy (Parpura et al., 1994; Araque et al., 1998a,b, 2014; Halassa et al., 2009a; Halassa and Haydon, 2010).

Increasing evidence indicates that astrocytes could be involved in the synchronization of cortical firing. Cortical circuits for sensory integration are known to display transient synchrony of neuronal ensembles (Harris et al., 2003; Haider and McCormick, 2009). The hallmark of this synchronized activity is the alternation of UP states—i.e., episodes of persistent neuronal firing lasting few milliseconds—and DOWN states—i.e., episodes of neuronal hyperpolarization (Steriade et al., 2001; Brecht and Sakmann, 2002; Cossart et al., 2003; Kenet et al., 2003). UP and DOWN states are common in a wide range of conditions, including quiescent wakefulness (Gentet et al., 2010), anesthesia (Steriade et al., 1993; Ramaswamy and Muller, 2015), and sleep itself (Massimini and Amzica, 2001). Moreover, astrocytes have been implicated in UP state genesis through the release of D-serine, adenosine and ATP (Fellin et al., 2009, 2012; Halassa et al., 2009b; Poskanzer and Yuste, 2011, 2016). Interestingly, gliotransmission has been proposed to operate on different time scales (Fellin et al., 2012). According to the Hill and Tononi's model of sleep and in agreement with the modulation cortical UP and DOWN states, Fellin and colleagues have demonstrated that the depolarizing effect of NMDA receptors currents preserves the UP state (Hill and Tononi, 2004; Fellin et al., 2012). Such a role for NMDA receptors is thought to be dependent on the availability of glia-released D-serine (Fellin et al., 2012), again demonstrating a prominent role of glia/neuron coupling.

Oligodendrocytes projections wrap neuronal axons forming the myelin sheaths in the central nervous system (CNS). These myelin sheaths insulate the fibers, and help them to carry the nerve impulses. Interestingly, myelin can influence conduction velocity of the electrical impulse by regulating the axon diameter, thickness of the myelin sheath, the number and spacing of nodes of Ranvier, and nodal structure and molecular composition of ion channels in the node and paranodal region (Berthold et al., 1983; Wurtz and Ellisman, 1986; Baker and Stryker, 1990; Carr and Konishi, 1990; Dupree et al., 2004). Taking this into a consideration, it has been shown that myelin specific proteins, including Nogo-A (Chen et al., 2000; GrandPré et al., 2000), myelin-associated glycoprotein (MAG; McKerracher et al., 1994) and oligodendrocyte-myelin glycoprotein (OMgp; Wang et al., 2002; Huang et al., 2005), inhibit directly axon sprouting and synaptogenesis and constrain nervous system plasticity. This finding indicates the participation of myelin in learning, memory, and cognition.

These glial cells are part of the brain's immune system and are mainly involved in the phagocytosis of foreign matter and cellular wastes of the CNS (Aloisi, 2001). Moreover, during postnatal development and adaptation to novel environments, microglia has a critical role in synaptic remodeling through the elimination of synapses and axon terminals. Additionally, increasing evidence points out that microglia could regulate synaptic plasticity and neurotransmission through the release of gliotransmitters (Batchelor et al., 1999, 2002; Zhong et al., 2010; Harry and Kraft, 2012; Sierra et al., 2013), as well as an increase hippocampal LTP and NMDA receptor-mediated responses via the secretion of glycine (Thomson et al., 1989; Abe et al., 1990; Hayashi et al., 2006). During neuroinflammation, microglia is capable to regulate excitatory neurotransmission by the rapid production of small amounts of ATP, that in turn, recruit astrocytes to augment ATP formation and Glu exocytosis enhancing synaptic transmission via metabotropic Glu receptors (Pascual et al., 2012). In fact, several reports reveal that some of the established astrocytic functions are regulated by the upstream activation of microglia (Ben Achour and Pascual, 2010; Pascual et al., 2012).

Gliotransmission is the process by which astrocytes interact with nearby neurons via the release of transmitters, like ATP and Glu (Haydon, 2001; Perea et al., 2009; Parpura and Zorec, 2010). Remarkably, ATP has been linked to modulation of LTP but also of synaptic depression (Gordon et al., 2005; Pascual et al., 2005; Bains and Oliet, 2007). In vivo, an astrocyte-dependent rhythmic ATP release is present in the SCN. Although the mechanisms responsible for these ATP oscillations are unknown, calcium-dependent signaling seems to be involved (Womac et al., 2009). Subsequently, it was shown that astrocytes display daily extracellular ATP oscillations that depend on the clock genes (Clock, Per, and Bmal1) and in inositol triphosphate (IP₃) signaling, indicating that extracellular ATP levels increase at a specific time of day and suggest a clock-induced increase in energy metabolism and glial activity, which participate in sleep-wake changes in the brain and in control synaptic transmission (Marpegan et al., 2011).

To date, there is no report demonstrating that the circadian clock regulates Glu release. In contrast, accumulating evidence indicates that the glutamate/aspartate transporter (Glast) gene expression and protein levels exhibit a diurnal rhythm in a light/dark 12/12 h cycle (Spanagel et al., 2005). These findings are consistent with the absence of rhythmicity of GLAST in the Per2 mutant mice, pointing out the presence of a circadian control (Spanagel et al., 2005). Later on, using cultured cortical astrocytes from Clock mutant animals, it was observed a marked decrease in Glast mRNA and protein levels, proposing that glial Glu uptake activity is a function of the clock genes: Clock, Npas2, and Per2 (Beaulé et al., 2009). Specifically, the dependence related to CLOCK and NPAS2 may be due to their involvement in Glast transcription, or in GLAST stability and/or localization (Danbolt, 2001). It is important to mention that no conclusive evidence has been shown for a circadian-dependent change in Glu uptake, suggesting a non-circadian role for clock proteins in Glast transcription or Glast mRNA translation and/or stability (Beaulé et al., 2009). However, it is clear that the regulation and precise function of this transporter is very important to guarantee an efficient glutamatergic neurotransmission. A failure in synaptic Glu clearance is neurotoxic due to a hyperactivation of postsynaptic Glu receptors resulting in the phenomena known as excitotoxicity, which is implicated in most of neurodegenerative diseases (McEntee and Crook, 1993; Domingues et al., 2010; Gegelashvili and Bjerrum, 2014).

In the adult brain, the distribution of the specific astrocyte marker, glial fibrillary acidic protein (GFAP), has been reported to peak during daily rhythms in the SCN (Lavialle and Servière, 1993). Furthermore, it has been demonstrated that this peak also prevails in constant darkness (Lavialle and Servière, 1993; Moriya et al., 2000), strongly suggesting that these rhythms are essential and independent of environmental light. Although the function of circadian fluctuations of GFAP immunoreactivity is unknown, it has been observed that mice lacking the gfap gene show reduced eyeblink training and impaired LTD in the cerebellum (Shibuki et al., 1996), suggesting that this protein plays a role in the regulation of neuronal functions.

CNS excitatory synapses are extremely dynamic structures that show stabilization in response to learning and memory process. These synapses are surrounded by intricate astrocytic processes denominated perisynaptic astrocytic processes (PAPs; Iino et al., 2001; Hirrlinger et al., 2004; Nishida and Okabe, 2007). It has been described in primary cultured astrocytes that ezrin (an actin-binding protein) is required for filopodia formation and motility of PAPs, such motility can be induced by Glu via activation of metabotropic Glu receptors 3 and 5 (Lavialle et al., 2011). Moreover, changes in glutamatergic circadian activity in the hamster SCN are in synchrony with changes in ezrin immunoreactivity which is consistent with Glu-induced perisynaptic glial motility (Lavialle et al., 2011). These results suggest that ezrin is essential for Glu-induced PAPs plasticity that could be regulated by circadian system.

On the other hand, the brain fatty-acid binding protein (FABP7) localizes in astrocytes and neuronal cell precursors in the mature brain, and presents a high binding affinity to long chain fatty acids whose effects on brain function include development, emotion, learning, and memory (Yamamoto et al., 1987; Jensen et al., 1996; Wainwright et al., 1997; Moriguchi et al., 2000; Takeuchi et al., 2003). Gerstner and colleagues demonstrated in adult murine brain that levels of Fabp7 mRNA oscillate over a 24 h period in brain areas that participate in daily activity and sleep like the hypothalamus, the tuberomammilary nucleus, the pons and the locus coeruleus. In these areas, Fabp7 diminish in the dark phase and increase instead in the light phase (Gerstner et al., 2006, 2008). In contrast with its mRNA levels, FABP7 levels are higher during the dark phase (Gerstner et al., 2008), indicating that expression of this protein is delayed by 12 h with regards to its mRNA. More recently, the same group demonstrated that FABP7 is specifically augmented in the perisynaptic compartment of fine astrocytic processes that surround synapses. Furthermore, CPEB-mediated cytoplasmic polyadenylation controls the diurnally regulated Fabp7 mRNA levels (Gerstner et al., 2012). Accordingly, in plasticity terms, targeting of Fabp7 and CPEB-mediated polyadenylation could participate in controlling astrocytic process extension, although it is unknown if variations in synaptic plasticity and/or neuronal activity modify polyadenylation and trafficking of Fabp7 mRNA resulting in morphological modifications of the astrocytic processes (Gerstner et al., 2012). In addition, variations in cycle-dependent memory formation and synaptic plasticity could regulate the circadian variations in subcellular trafficking and localization of Fabp7 mRNA in hippocampal tripartite synapses (Gerstner et al., 2009, 2012).

To date, there is no evidence that oligodendrocytes have an internal circadian clock; however, it has been reported that oligodendrocytes precursor cells (OPCs) proliferation in the hippocampus could be regulated by clock genes (Matsumoto et al., 2011). It should be noted that OPCs proliferation itself could modulate the synaptic plasticity of the hippocampus in response to neuronal activity, thus circadian proliferation of these cells could regulate hippocampal function. Particularly, the OPCs give rise to mature oligodendrocytes, and are thought to be a constitutive reservoir of oligodendrocytes that replace damaged myelin (Levine et al., 1993) or add de novo myelination (McCarthy and Leblond, 1988). Interestingly, myelin proteolipid protein (plp), a myelin-specific gene, is regulated by Clock (Du et al., 2005), suggesting that the circadian clock controls myelin formation.

Microglial cells constantly retract and extend their processes to sense their local environment contributing to the maintenance of healthy neuronal circuits (Kirchhoff, 2013). There is evidence that an intrinsic molecular clock exists in cortical microglia which controls diurnal morphological changes of its processes, and whereby these cells regulate the sleep-wake cycle-dependent changes in synaptic strength (Hayashi et al., 2013a,b). In line with these findings, it has been reported that the microglia-specific lysosomal cysteine protease Cathepsin S (CatS) exhibits a circadian expression in cortical microglia. The expression of CatS is involved in diurnal variations of synaptic strength in cortical neurons via the proteolytic modification of the perineuronal environment. However, disruptions in CatS lead to hyperlocomotor activity and to the deletion of the diurnal variations in spine density and synaptic activity of these cortical neurons as a consequence of the failure to downscale synaptic strength during sleep (Hayashi et al., 2013a). Since downscaling of synaptic strength is required for the acquisition and consolidation of novel information upon awakening, it is evident that dysfunction of the microglial intrinsic circadian clock is involved in neuropsychiatric disorders based on sleep disturbance, including depression and cognitive impairment (Bhattacharjee, 2007; Hayashi et al., 2014).

On the other hand, microglial cells express ATP receptors of the P2X (P2XR, ligand-gated ion-channel receptor) and P2Y subtypes (P2YR, G protein-coupled receptor). ATP released by glial cells during neuronal activity is then, capable to influence synaptic transmission. In fact in microglial cells, ATP increases the number their branch points, extension of their processes and morphological complexity (Fontainhas et al., 2011). Specifically, it has been demonstrated that the degree of microglial process extension is controlled by microglial P2Y₁₂Rs (Haynes et al., 2006). Moreover, Hayashi and colleagues reported that microglial P2Y₁₂Rs present circadian oscillations regardless that microglia would be isolated under constant darkness conditions (Hayashi et al., 2013b). Interestingly, inhibition of these purinergic receptors disrupts the rhythmic patterns of synaptic strength or spine density, while upregulated P2Y₁₂Rs during the dark phase results in extension of the microglial processes that are partially retracted during the light phase resulting in a decrease of synaptic strength or spine density (Hayashi et al., 2013b). In the same fashion of CatS disruptions, dysfunctions in microglia-synapse interactions participate in neuropsychiatric disorders (Bhattacharjee, 2007; Hayashi et al., 2014).

Concerning P2X purinergic receptors, Nakazato and coworkers demonstrated that ATP selectively promotes the expression of the protein and mRNA of Per1 through the activation of P2X7R in microglial cells (Nakazato et al., 2011). While the outcome of this upregulation is not completely clear, it has been reported that Per is not only crucial for long-term memory formation (LTM), but overexpression of this gene also enhances memory formation (Sakai et al., 2004). Taken together these evidences suggest that Per has an important function in the regulation of circadian synaptic plasticity in microglia.

Additionally, several reports indicate that ATP promotes microglial cells to secrete several signaling molecules, like interleukin-1 beta (IL-1β), TNFα, and plasminogen (Inoue et al., 1998; Hide et al., 2000; Sanz and Di Virgilio, 2000; Suzuki et al., 2004); which are involved in the modulation of synaptic transmission and plasticity (Ikegaya et al., 2003; Becker et al., 2013; Liu et al., 2014). Finally, it should be noted that microglia display rhythmic fluctuations in the gene expression of these mediators (Fonken et al., 2015).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.