Table 1.
Summary of evidence supporting involvement of extracellular interacting proteins and molecules in the SCN circadian system and sleep-wake system.
| Protein | General function | Circadian Rhythm Effects in SCN | Sleep Effects Across Brain Regions | Citations |
|---|---|---|---|---|
| CAMs & related | ||||
| EphA4 | Cell adhesion molecule | Disrupted circadian function in EphA4-/- mice; necessary for maintenance and entrainment of circadian clocks, expressed in SCN and expression decreases in Clock mutant mice | EphA4-/- mice display reduced REMS, and reduced NREMS. | Kiessling et al., 2017; Freyburger et al., 2016 |
| Ephrin B3 | Cell adhesion molecule | Unknown | Sleep deprivation decreases expression of Ephrin B3 in forebrain and cortex. | Mongrain et al., 2010; Mackiewicz et al., 2007; O'Callaghan et al., 2017 |
| Integrins | Cell adhesion molecule | Unknown | Increased levels of αM integrin in human saliva after 30 h sleep loss; sleep deprivation decreases Integrin α4 and increases Integrin α10; sleep deprivation in Drosophila increases α5-integrin expression; sleep induces changes in integrin mRNA expression in cortex | Thimgan et al., 2013; O'Callaghan et al., 2017; Mackiewicz et al., 2007; Mongrain et al., 2010 |
| L1-CAM | Cell adhesion molecule | Infusion disrupts circadian phase shifts and SCN architecture | unknown | Yamada et al., 1999; Yamada et al., 2003 |
| (PSA)-NCAM | Cell adhesion molecule | Induced by light and involved in circadian clock entrainment; removal of PSA disrupts circadian rhythms; protein expression high during day, low at night; localized to neuronal somas and astrocytic fine processes in SCN | Expressed in hypothalamus, brainstem, VLPO, ventrolateral periaqueductal grey; increased immunoreactivity in median eminence after sleep deprivation; removal of PSA in brain decreases REMS, decreases REMS episodes and shortens mean duration of REMS | Shen et al., 1999; Glass et al., 2000; Prosser et al., 2003; Fedorkova et al., 2002; Glass et al., 2003; Shen et al., 2001; Glass et al., 2004; Black et al., 2009; Bokiniec et al., 2017 |
| Neurexins | Presynaptic CAM | Circadian rhythm in neurexin 2α gene transcription | dNrx1 gene inactivation and neurexin deletion decreases sleep in Drosophila | Shapiro-Reznik et al., 2012; Tong et al 2016; Larkin et al., 2015 |
| Neuroligins | Postsynaptic CAM | Binding of BMAL1 and CLOCK exhibits diurnal rhythm in forebrain | Sleep deprivation influences expression levels of Nlg1and Nlg2; Nlg1 knockout mice have decreased wakefullness/increased SWS; Missense mutation in Nlg3 alters EEG spectral profiles; dNlg4 regulates sleep in Drosophila | Matsuki et al 2015; El Helou et al., 2013; Massart et al. 2014; Liu et al 2017; Li et al., 2013 |
| Shank3 | Postsynaptic scaffolding protein | Time-of-day dependent rhythms in expression | Patients with epileptic seizures during SWS have variations in copy number of Shank3 gene | Sarowar et al., 2016; Lesca et al., 2012 |
| Extracellular protease-related | ||||
| BDNF | Growth factor | Heterozygous knockout mice have reduced photic phase shifts; needed for glutamate-induced phase shifting; allows photic phase shifts during the day; mRNA and protein are high at night, low during the day | Cortical mRNA levels increase after sleep deprivation; injections of BDNF increase SWS in mice; in PPT and subcoeruleus nucleus, protein expression increases after REMS disruption | Mou et al., 2009; Liang et al., 1998; Liang et al., 2000; Michel et al., 2006; Taishi et al., 2001; Datta et al. 2015; Barnes et al., 2017; Faraguna et al., 2008; Mou et al., 2009 |
| LRP-1 | Membrane bound receptor | Expressed in the SCN; required for glutamate-induced phase shifts in vitro; heavy chain portion expression is high at night, low in day | Sleep deprivation decreases soluble LRP-1 levels in blood plasma; LRP-1 mRNA increases in cortex during sleep | Cooper & Prosser, 2014; Wei et al. 2017; Mackiewicz et al., 2007 |
| MMP-2/9 | Proteases | Expressed in the SCN; inhibiting induces phase shifts; protein expression not rhythmic; decreased MMP9 activity at ZT23 | Cortical/hippocampal mRNA levels decrease after sleep deprivation | Halter and Prosser, submitted for publication; Taishi et al., 2001 |
| Neuroserpin | Inhibits tPA/uPA | Protein expression is high in day, low at night; neuroserpin antibody allows glutamate phase shifts in the day in vitro | Unknown | Prosser & Conner, unpublished data |
| PAI-1 | Inhibitor of tPA | Expressed in the SCN; blocks glutamate induced phase shifts in vitro | Increased expression in blood of female shift workers with poor sleep quality | Mou et al., 2009; Nadir et al. 2015 |
| Plasmin | Cleave BDNF | Expressed in the SCN; inhibiting blocks glutamate-induced phase shift | Unknown | Mou et al., 2009 |
| tPA | Cleave plasminogen | Involved in glutamate-induced phase shifting; influences food anticipatory behavior; rhythmic protein expression in vitro with higher levels at night | In mice, cortical mRNA levels increase after sleep deprivation | Taishi et al., 2001; Mou et al., 2009; Cooper et al., 2017; Krizo et al., 2018 |
| TrkB | Membrane bound receptor of BDNF | Important for glutamate-induced phase resetting | Inhibiting PPT reduces REM sleep, suggesting TrkB activation is necessary for increase in REMS homeostatic drive; truncated TrkB, lacking kinase domain, increases total REMS and decreases latency to REMS | Mou et al., 2009; Barnes et al. 2017; Liang et al., 2000; Michel et al., 2006; Watson et al., 2015 |
| uPA | Cleave plasminogen | Supports phase shift in absence of tPA; no circadian rhythm detected in vitro | Unknown | Cooper et al., 2017 |
| Vitronectin | ECM Molecule | Regulation of tPA by PAI-1 requires VN | Unknown | Mou et al., 2009 |
| Gliotransmitters | ||||
| Adenosine | Nucleoside | Adenosine acting on A1 receptors can phase-shift the SCN clock and block photic phase shifts; at least some actions involve inhibiting glutamate release | Inhibits wake-promoting neurons via A2a receptors; lack of adenosine increases SWS time and enhances SWS after sleep deprivation; astrocyte-derived adenosine modulates sleep; glucose stimulates astrocytic release of adenosine in VLPO | Huang et al., 2014; Womac et al., 2009; Antle et al., 2001; Watanabe et al., 1996; Elliott et al., 2001; Sigworth and Rea, 2003; Hallworth et al., 2002; Halassa et al., 2009; Blutstein and Haydon, 2013; Scharbarg et al., 2017 |
| ATP | Nucleotide | Genes involved in ATP regulation exhibit circadian rhythms; circadian variation in production and accumulation of extracellular ATP in SCN2.2 cells and rat in vivo | Mice lacking pannexin-1 channel have inverted wake/SWS ratio and increased activity in light and dark. ATP agonists increase SWS in mice. ATP PX27 receptor expression varies with sleep state. ATP increases astrocytic release of IL1β and TNFα. | Menger et al., 2005; Womac et al., 2009; Kovalzon et al., 2017; Krueger et al, 2010; Krueger et al., 2011; Jewett and Krueger, 2012. |
| Interleukins | Cytokines | IL1β and IL-6 exhibit circadian patterns of expression in human plasma. Decreased Per and Cry expression in liver, fibroblasts and neuronal cell cultures and decrease behavioral activity in mice. Peak mRNA expression during light phase. Hippocampal microglia exhibit diurnal expression of IL1β. | IL1β protein and mRNA levels increase during wakefulness and decrease during sleep.Low doses of IL1β increase SWS while high doses suppress SWS and REMS. Mice lacking IL1β receptors have less SWS and REMS during active period. Sleep regulatory regions in the brain (cortex, brainstem and hypothalamus) contain glia expressing IL1β. Selective expression of IL1β receptor to neurons or astrocytes prevents IL1β-induced increases in sleep. Astrocytic IL1β receptors required for proper REM, NREM sleep, and production of IL-6 protein in the hypothalamus. IL-6 increases in mice that experienced sleep fragmentation. | Bauer et al., 1994; Vgontzas et al., 1997, Vgontzas et al., 2005; Cearley et al., 2013; Taishi et al., 1997; Vacas et al., 2017; Fonken et al., 2015; Fonken et al., 2015; Imeri and Opp, 2009; Del Gallo and Opp, 2014. Ingiosi et al., 2015; Ingiosi and Opp, 2016. Krueger et al., 2011. |
| TNFα | Cytokine | Plasma expression of TNFα exhibits circadian rhythms; regulates LPS-induced phase shifts of locomotor activity rhythms in mice; decreases Per and Cry expression in liver, fibroblasts and neuronal cell cultures and behavioral activity in mice. Peak mRNA expression during light phase. TNFα decreases expression of Dpb mRNA in SCN tissue. TNFα shifts PER2 rhythms in SCN astrocyte cultures. Hippocampal microglia exhibit diurnal expression of TNFα. | Wakefulness increases mRNA and protein expression of TNFα while inhibiting its activity can decrease sleep. Increases in TNFα accompany sleep fragmentation and decreased sleep quality in mice and humans. TNFα is expressed by glia in sleep regulatory regions of the brain (cortex, brainstem, and hypothalamus). TNFα receptor knockouts exhibit decreased SWS and REMS late in their active period and entire sleep period. Increases and fragments NREM sleep, inhibits REM sleep. TNFα enhances sleep like states (i.e. burstiness, synchronization and slow wave power) of cultured cortical astrocytes. | Born et al. 1997; Bredow et al. 1997; Cearley et al., 2013; Cavadini et al., 2007; Gast et al., 2012; Vacas et al., 2017; Duhart et al., 2013; Fonken et al., 2015; Fonken et al., 2015; Imeri and Opp, 2009; Jewett et al., 2015. Krueger et al., 2011. |
| Nitric oxide | Secreted gaseous molecule | Found in SCN astrocytes; modulates photic transduction; hemoglobin scavenging of NO blocks some but not all circadian effects | Wakefullness and sleep deprivation increase NO production by NOS; Nos3 expression in cerebral cortex increases during sleep; nNOS-/- mice have decreased SWS; in sleep deprived mice nNOS inhibition in basal forebrain decreases REM sleep recovery while iNOS inhibition prevents SWS recovery | Ding et al., 1994; Golombek et al., 2004; Plano et al., 2010; Artinian et al., 2001; Caillol et al., 2000; Brown et al., 2012; Mackiewicz et al., 2007; Morairty et al. 2013; Kalinchuk et al., 2006 |