Molecular Mechanisms of Sleep and Wakefulness
Miroslaw Mackiewicz,
Nirinjini Naidoo,
John E. Zimmerman,
Allan I. Pack,
Miroslaw Mackiewicz
Center for Sleep and Respiratory Neurobiology, Division of Sleep Medicine/Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Search for more papers by this authorNirinjini Naidoo
Center for Sleep and Respiratory Neurobiology, Division of Sleep Medicine/Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Search for more papers by this authorJohn E. Zimmerman
Center for Sleep and Respiratory Neurobiology, Division of Sleep Medicine/Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Search for more papers by this authorAllan I. Pack
Center for Sleep and Respiratory Neurobiology, Division of Sleep Medicine/Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Search for more papers by this authorMiroslaw Mackiewicz,
Nirinjini Naidoo,
John E. Zimmerman,
Allan I. Pack,
Miroslaw Mackiewicz
Center for Sleep and Respiratory Neurobiology, Division of Sleep Medicine/Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Search for more papers by this authorNirinjini Naidoo
Center for Sleep and Respiratory Neurobiology, Division of Sleep Medicine/Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Search for more papers by this authorJohn E. Zimmerman
Center for Sleep and Respiratory Neurobiology, Division of Sleep Medicine/Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Search for more papers by this authorAllan I. Pack
Center for Sleep and Respiratory Neurobiology, Division of Sleep Medicine/Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Search for more papers by this authorAddress for correspondence: Allan I. Pack, M.B., Ch.B., Ph.D., Center for Sleep and Respiratory Neurobiology, 125 South 31st Street, Suite 2100, Philadelphia, PA 19104-3403. Voice: +1-215-746-4806; fax: +1-215-746-4814. [email protected]
Abstract
Major questions on the biology of sleep include the following: what are the molecular functions of sleep; why can wakefulness only be sustained for defined periods before there is behavioral impairment; what genes contribute to the individual differences in sleep and the response to sleep deprivation? Behavioral criteria to define sleep have facilitated identification of sleep states in a number of different model systems: Drosophila, zebrafish, and Caenorhabditis elegans. Each system has unique strengths. Studies in these model systems are identifying conserved signaling mechanisms regulating sleep that are present in mammals. For example, the PKA-CREB signaling mechanism promotes wakefulness in Drosophila, mice, and C. elegans. Microarray studies indicate that genes whose expression is upregulated during sleep are involved in macromolecule biosynthesis (proteins, lipids [including cholesterol], heme). Thus, a key function of sleep is likely to be macromolecule synthesis. Moreover, in all species studied to date, there is upregulation of the molecular chaperone BiP with extended wakefulness. Sleep deprivation leads to cellular ER stress in brain and the unfolded protein response. Identification of genes regulating sleep has the potential for translational studies to elucidate the genetics of sleep and response to sleep deprivation in humans.
References
- 1
Shaw, P.J.
et al
. 2000. Correlates of sleep and waking in Drosophila melanogaster.
Science
287: 1834–1837.
- 2
Hendricks, J.C.
et al
. 2000. Rest in Drosophila is a sleep-like state.
Neuron.
25: 129–138.
- 3
Yokogawa, T.
et al
. 2007. Characterization of sleep in zebrafish and insomnia in hypocretin receptor mutants.
PLoS Biol.
5: 2379–2397.
- 4
Prober, D.A.
et al
. 2006. Hypocretin/orexin overexpression induces an insomnia-like phenotype in zebrafish.
J. Neurosci.
26: 13400–13410.
- 5
Zhdanova, I.V.
et al
. 2001. Melatonin promotes sleep-like state in zebrafish.
Brain Res.
903: 263–268.
- 6
Raizen, D.M.
et al
. 2008. Lethargus in C. elegans is a sleep-like state.
Nature, in press.
- 7
Swanson, K.S.
et al
. 2004. Genomics and clinical medicine: rationale for creating and effectively evaluating animal models.
Exp. Biol. Med. (Maywood)
229: 866–875.
- 8
Mackiewicz, M. &
A.I. Pack. 2003. Functional genomics of sleep.
Respir. Physiol. Neurobiol.
135: 207–220.
- 9
Hendricks, J.C.
2005. Shaking up sleep research.
Nat. Neurosci.
8: 703–705.
- 10
Hendricks, J.C.,
A. Sehgal &
A.I. Pack. 2000. The need for a simple animal model to understand sleep.
Prog. Neurobiol.
61: 339–351.
- 11
Gill, T.J., 3rd
et al
. 1989. The rat as an experimental animal.
Science
245: 269–276.
- 12
Jacob, H.J.
1999. Physiological genetics: application to hypertension research.
Clin. Exp. Pharmacol. Physiol.
26: 530–535.
- 13
Jacob, H.J.
1999. Functional genomics and rat models.
Genome Res.
9: 1013–1016.
- 14
Jacob, H.J. &
A.E. Kwitek. 2002. Rat genetics: attaching physiology and pharmacology to the genome.
Nat. Rev. Genet.
3: 33–42.
- 15
Cowley, A.W., Jr.
et al
. 2004. Consomic rat model systems for physiological genomics.
Acta Physiol. Scand.
181: 585–592.
- 16
Malek, R.L.
et al
. 2006. Physiogenomic resources for rat models of heart, lung and blood disorders.
Nat. Genet.
38: 234–239.
- 17
Nobrega, M.A.
et al
. 2004. Initial characterization of a rat model of diabetic nephropathy.
Diabetes
53: 735–742.
- 18
Roman, R.J.
et al
. 2002. Consomic rats for the identification of genes and pathways underlying cardiovascular disease.
Cold Spring Harb. Symp. Quant. Biol.
67: 309–315.
- 19
Twigger, S.N.
et al
. 2007. The Rat Genome Database, update 2007–easing the path from disease to data and back again.
Nucleic Acids Res.
35: D658–662.
- 20
Cirelli, C. &
G. Tononi. 2000. On the functional significance of c-fos induction during the sleep-waking cycle.
Sleep
23: 453–469.
- 21
Sherin, J.E.
et al
. 1996. Activation of ventrolateral preoptic neurons during sleep.
Science
271: 216–219.
- 22
Sherin, J.E.
et al
. 1998. Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat.
J. Neurosci.
18: 4705–4721.
- 23
Saper, C.B.,
G. Cano &
T.E. Scammell. 2005. Homeostatic, circadian, and emotional regulation of sleep.
J. Comp. Neurol.
493: 92–98.
- 24
Saper, C.B.,
T.C. Chou &
T.E. Scammell. 2001. The sleep switch: hypothalamic control of sleep and wakefulness.
Trends Neurosci.
24: 726–731.
- 25
Gvilia, I.
et al
. 2006. Homeostatic regulation of sleep: a role for preoptic area neurons.
J. Neurosci.
26: 9426–9433.
- 26
McGinty, D. &
R. Szymusiak. 2003. Hypothalamic regulation of sleep and arousal.
Front Biosci.
8: s1074–1083.
- 27
Szymusiak, R.,
I. Gvilia &
D. McGinty. 2007. Hypothalamic control of sleep.
Sleep Med.
8: 291–301.
- 28
Lu, J.,
T.C. Jhou &
C.B. Saper. 2006. Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray matter.
J. Neurosci.
26: 193–202.
- 29
Colten, H.R. &
B.M. Altevogt. 2006. Sleep disorders and sleep deprivation: an unmet public health problem. The National Academies Press.
Washington
,
DC
.
- 30
Sauer, B.
1998. Inducible gene targeting in mice using the Cre/lox system.
Methods
14: 381–392.
- 31
Gong, S.
et al
. 2003. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes.
Nature
425: 917–925.
- 32
Heintz, N.
2004. Gene expression nervous system atlas (GENSAT).
Nat. Neurosci.
7: 483.
- 33
Nadeau, J.H.
et al
. 2000. Analysing complex genetic traits with chromosome substitution strains.
Nat. Genet.
24: 221–225.
- 34
Singer, J.B.
et al
. 2004. Genetic dissection of complex traits with chromosome substitution strains of mice.
Science
304: 445–448.
- 35
Taylor, B.
1989. Recombinant inbred strains.
In
Genetic Variants and Strains of the Laboratory Mouse. M. Lyon, Ed.: 773–796. Oxford University Press.
Oxford
.
- 36
Bailey, D.
1981. Strategic uses of recombinant inbred and con-genic strains in behavior genetics research.
In
Genetic Research Strategies for Psychogiology and Psychiatry. E.S. Gershon,
M.S.,
X.O. Breakefield &
E.D. Ciaranello, Eds.: 189–198. Plenum.
New York
.
- 37
Cuppen, E.
2005. Haplotype-based genetics in mice and rats.
Trends Genet.
21: 318–322.
- 38
DiPetrillo, K.
et al
. 2005. Bioinformatics toolbox for narrowing rodent quantitative trait loci.
Trends Genet.
21: 683–692.
- 39
Wang, X.
et al
. 2005. Identifying novel genes for atherosclerosis through mouse-human comparative genetics.
Am. J. Hum. Genet.
77: 1–15.
- 40
Wang, X. &
B. Paigen. 2005. Genome-wide search for new genes controlling plasma lipid concentrations in mice and humans.
Curr. Opin. Lipidol.
16: 127–137.
- 41
Tobler, I.,
T. Deboer &
M. Fischer. 1997. Sleep and sleep regulation in normal and prion protein-deficient mice.
J. Neurosci.
17: 1869–1879.
- 42
Tobler, I.
et al
. 1996. Altered circadian activity rhythms and sleep in mice devoid of prion protein.
Nature
380: 639–642.
- 43
Franken, P.
et al
. 2000. The transcription factor DBP affects circadian sleep consolidation and rhythmic EEG activity.
J. Neurosci.
20: 617–625.
- 44
Laposky, A.D.
et al
. 2006. Altered sleep regulation in leptin-deficient mice.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
290: R894–903.
- 45
Fang, J.,
Y. Wang &
J.M. Krueger. 1998. Effects of interleukin-1 beta on sleep are mediated by the type I receptor.
Am. J. Physiol.
274: R655–660.
- 46
Naylor, E.
et al
. 2000. The circadian clock mutation alters sleep homeostasis in the mouse.
J. Neurosci.
20: 8138–8143.
- 47
Zhang, J.
et al
. 1996. Non-rapid eye movement sleep is suppressed in transgenic mice with a deficiency in the somatotropic system.
Neurosci. Lett.
220: 97–100.
- 48
Shiromani, P.J.
et al
. 2000. Sleep and wakefulness in c-fos and fos B gene knockout mice.
Brain Res. Mol. Brain Res.
80: 75–87.
- 49
Toth, L.A. &
M.R. Opp. 2001. Cytokine- and microbially induced sleep responses of interleukin-10 deficient mice.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
280: R1806–1814.
- 50
Wisor, J.P.
et al
. 2005. Sleep and circadian abnormalities in a transgenic mouse model of Alzheimer's disease: a role for cholinergic transmission.
NeuroScience
131: 375–385.
- 51
Lee, J.,
D. Kim &
H.S. Shin. 2004. Lack of delta waves and sleep disturbances during non-rapid eye movement sleep in mice lacking alpha1G-subunit of T-type calcium channels.
Proc. Natl. Acad. Sci. U. S. A.
101: 18195–18199.
- 52
Chemelli, R.M.
et al
. 1999. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation.
Cell.
98: 437–451.
- 53
Hara, J.
et al
. 2001. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity.
Neuron.
30: 345–354.
- 54
Goutagny, R.
et al
. 2005. Paradoxical sleep in mice lacking M3 and M2/M4 muscarinic receptors.
Neuropsychobiology
52: 140–146.
- 55
Mignot, E.
2004. Sleep, sleep disorders and hypocretin (orexin).
Sleep Med.
5(Suppl 1): S2–8.
- 56
Yang, Z. &
A. Sehgal. 2001. Role of molecular oscillations in generating behavioral rhythms in Drosophila.
Neuron.
29: 453–467.
- 57
Dunlap, J.C.
1999. Molecular bases for circadian clocks.
Cell.
96: 271–290.
- 58
Hall, J.C.
2003. Genetics and molecular biology of rhythms in Drosophila and other insects.
Adv. Genet.
48: 1–280.
- 59
Williams, J.A. &
A. Sehgal. 2001. Molecular components of the circadian system in Drosophila.
Annu. Rev. Physiol.
63: 729–755.
- 60
Tobler, I.
1983. Effect of forced locomotion on the rest-activity cycle of the cockroach.
Behav. Brain Res.
8: 351–360.
- 61
Tobler, I. &
A.A. Borbely. 1985. Effect of rest deprivation on motor activity of fish.
J. Comp. Physiol. [A]
157: 817–822.
- 62
Tobler, I.I. &
M. Neuner-Jehle. 1992. 24-h variation of vigilance in the cockroach Blaberus giganteus.
J. Sleep Res.
1: 231–239.
- 63
Chen, E. &
S.C. Ekker. 2004. Zebrafish as a genomics research model.
Curr. Pharm. Biotechnol.
5: 409–413.
- 64
Dooley, K. &
L.I. Zon. 2000. Zebrafish: a model system for the study of human disease.
Curr. Opin. Genet. Dev.
10: 252–256.
- 65
Faraco, J.H.
et al
. 2006. Regulation of hypocretin (orexin) expression in embryonic zebrafish.
J. Biol. Chem.
281: 29753–29761.
- 66
McGuire, S.E.,
Z. Mao &
R.L. Davis. 2004. Spatiotemporal gene expression targeting with the TARGET and gene-switch systems in Drosophila.
Sci STKE
2004: l6.
- 67
Roman, G. &
R.L. Davis. 2002. Conditional expression of UAS-transgenes in the adult eye with a new gene-switch vector system.
Genesis
34: 127–131.
- 68
Ryder, E. &
S. Russell. 2003. Transposable elements as tools for genomics and genetics in Drosophila.
Brief Funct. Genomic Proteomic
2: 57–71.
- 69
Cirelli, C.
et al
. 2005. Reduced sleep in Drosophila Shaker mutants.
Nature
434: 1087–1092.
- 70
Douglas, C.L.
et al
. 2007. Sleep in Kcna2 knockout mice.
BMC Biol.
5: 42.
- 71
Hendricks, J.C.
et al
. 2001. A non-circadian role for cAMP signaling and CREB activity in Drosophila rest homeostasis.
Nat. Neurosci.
4: 1108–1115.
- 72
Hummler, E.
et al
. 1994. Targeted mutation of the CREB gene: compensation within the CREB/ATF family of transcription factors.
Proc. Natl. Acad. Sci. USA
91: 5647–5651.
- 73
Graves, L.
et al
. 2002. Behavioral analysis of CREB alphadelta mutation on a B6/129 F1 hybrid background.
Hippocampus
12: 18–26.
- 74
Graves, L.A.
et al
. 2003. Genetic evidence for a role of CREB in sustained cortical arousal.
J. Neurophysiol.
90: 1152–1159.
- 75
Borbely, A.A. &
P. Achermann. 1999. Sleep homeostasis and models of sleep regulation.
J. Biol. Rhythms.
14: 557–568.
- 76
Raizen, D.M.
et al
. 2007. Lethargus in C. elegans is a sleep-like state.
In
Society for Neuroscience, Vol. Program No. 22.3.
San Diego
,
CA
.
- 77
Ruvkun, G.
1997. Patterning the nervous system. Cold Spring Harbor Laboratory Press.
Cold Spring Harbor
,
NY
.
- 78
Melkman, T. &
P. Sengupta. 2004. The worm's sense of smell. Development of functional diversity in the chemosensory system of Caenorhabditis elegans.
Dev. Biol.
265: 302–319.
- 79
Raizen, D.M.
et al
. 2006. A novel gain-of-function mutant of the cyclic GMP-dependent protein kinase egl-4 affects multiple physiological processes in Caenorhabditis elegans.
Genetics
173: 177–187.
- 80
Steriade, M.,
D.A. McCormick &
T.J. Sejnowski. 1993. Thalamocortical oscillations in the sleeping and aroused brain.
Science
262: 679–685.
- 81
Pack, A.I.
et al
. 2007. Novel method for high-throughput phenotyping of sleep in mice.
Physiol. Genomics.
28: 232–238.
- 82
Flores, A.E.
et al
. 2007. Pattern recognition of sleep in rodents using piezoelectric signals generated by gross body movements.
IEEE Trans. Biomed. Eng.
54: 225–233.
- 83
Battey, J.
et al
. 1999. An action plan for mouse genomics.
Nat. Genet.
21: 73–75.
- 84
Austin, C.P.
2004. The knockout mouse project.
Nat. Genet.
36: 921–924.
- 85
Abiola, O.
et al
. 2003. The nature and identification of quantitative trait loci: a community's view.
Nat. Rev. Genet.
4: 911–916.
- 86
Andretic, R. &
P.J. Shaw. 2005. Essentials of sleep recordings in Drosophila: moving beyond sleep time.
Methods Enzymol.
393: 759–772.
- 87
Zimmerman, J.
et al
. 2007. A video based method to study sleep in Drosophila melanogaster.
Sleep
30: A351.
- 88
Borbely, A.A.
1982. A two process model of sleep regulation.
Hum. Neurobiol.
1: 195–204.
- 89
Tobler, I. &
A.A. Borbely. 1986. Sleep EEG in the rat as a function of prior waking.
Electroencephalogr. Clin. Neurophysiol.
64: 74–76.
- 90
Tobler, I. &
A.A. Borbely. 1990. The effect of 3-h and 6-h sleep deprivation on sleep and EEG spectra of the rat.
Behav. Brain Res.
36: 73–78.
- 91
Huber, R.,
G. Tononi &
C. Cirelli. 2007. Exploratory behavior, cortical BDNF expression, and sleep homeostasis.
Sleep
30: 129–139.
- 92
Genoud, C.
et al
. 2004. Altered synapse formation in the adult somatosensory cortex of brain-derived neurotrophic factor heterozygote mice.
J. Neurosci.
24: 2394–2400.
- 93
Bosman, L.W.
et al
. 2006. Requirement of TrkB for synapse elimination in developing cerebellar Purkinje cells.
Brain Cell. Biol.
35: 87–101.
- 94
Carter, A.R.
et al
. 2002. Brain-derived neurotrophic factor modulates cerebellar plasticity and synaptic ultrastructure.
J. Neurosci.
22: 1316–1327.
- 95
Tononi, G. &
C. Cirelli. 2003. Sleep and synaptic homeostasis: a hypothesis.
Brain Res. Bull.
62: 143–150.
- 96
Tononi, G. &
C. Cirelli. 2006. Sleep function and synaptic homeostasis.
Sleep Med. Rev.
10: 49–62.
- 97
Cirelli, C.,
C.M. Gutierrez &
G. Tononi. 2004. Extensive and divergent effects of sleep and wakefulness on brain gene expression.
Neuron.
41: 35–43.
- 98
Cirelli, C. &
G. Tononi. 1998. Differences in gene expression between sleep and waking as revealed by mRNA differential display.
Brain Res. Mol. Brain Res.
56: 293–305.
- 99
Cirelli, C. &
G. Tononi. 2000. Gene expression in the brain across the sleep-waking cycle.
Brain Res.
885: 303–321.
- 100
Cirelli, C. &
G. Tononi. 1999. Differences in brain gene expression between sleep and waking as revealed by mRNA differential display and cDNA microarray technology.
J. Sleep Res.
8(Suppl 1): 44–52.
- 101
Terao, A.
et al
. 2003. Differential increase in the expression of heat shock protein family members during sleep deprivation and during sleep.
NeuroScience
116: 187–200.
- 102
Terao, A.
et al
. 2006. Gene expression in the rat brain during sleep deprivation and recovery sleep: an Affymetrix GeneChip study.
NeuroScience
137: 593–605.
- 103
Cirelli, C.,
T.M. LaVaute &
G. Tononi. 2005. Sleep and wakefulness modulate gene expression in Drosophila.
J. Neurochem.
94: 1411–1419.
- 104
Mackiewicz, M.
et al
. 2007. Macromolecule biosynthesis - a key function of sleep.
Physiol. Genomics.
- 105
Zimmerman, J.E.
et al
. 2006. Multiple mechanisms limit the duration of wakefulness in Drosophila brain.
Physiol. Genomics
27: 337–350.
- 106
Benington, J.H. &
H.C. Heller. 1995. Restoration of brain energy metabolism as the function of sleep.
Prog. Neurobiol.
45: 347–360.
- 107
Borbely, A.A. &
I. Tobler. 1989. Endogenous sleep-promoting substances and sleep regulation.
Physiol. Rev.
69: 605–670.
- 108
Cirelli, C.,
C.M. Gutierrez &
G. Tononi. 2004. Extensive and divergent effects of sleep and wakefulness on brain gene expression.
Neuron.
41: 35–43.
- 109
Jones, S.
et al
. 2007. Sleep and wakefulness-related changes in gene expression in the avian brain.
Sleep
30: A4.
- 110
Naidoo, N.
et al
. 2005. Sleep deprivation induces the unfolded protein response in mouse cerebral cortex.
J. Neurochem.
92: 1150–1157.
- 111
Naidoo, N.
et al
. 2007. A role for the molecular chaperone protein BiP/GRP78 in Drosophila sleep homeostasis.
Sleep
30: 557–565.
- 112
Naidoo, N.
et al
. 2005. Sleep deprivation induces theUnfolded Protein Response in mouse cerebral cortex.
J. Neurochemistry
92: 1150–1157.
- 113
Kaufman, R.J.
2002. Orchestrating the unfolded protein response in health and disease.
J. Clin. Invest.
110: 1389–1398.
- 114
Ma, Y. &
L.M. Hendershot. 2002. The mammalian endoplasmic reticulum as a sensor for cellular stress.
Cell. Stress Chaperones
7: 222–229.
- 115
Harding, H.P. &
D. Ron. 2002. Endoplasmic reticulum stress and the development of diabetes: a review.
Diabetes
51(Suppl 3): S455–461.
- 116
Zhang, K. &
R.J. Kaufman. 2004. Signaling the unfolded protein response from the endoplasmic reticulum.
J. Biol. Chem.
279: 25935–25938.
- 117
Schroder, M. &
R.J. Kaufman. 2005. The mammalian unfolded protein response.
Annu. Rev. Biochem.
74: 739–789.
- 118
Schroder, M. &
R.J. Kaufman. 2005. ER stress and the unfolded protein response.
Mutat. Res.
569: 29–63.
- 119
Bertolotti, A.
et al
. 2000. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response.
Nature Cell. Biology
2: 326–332.
- 120
Shen, Y.,
L. Meunier &
L.M. Hendershot. 2002. Identification and characterization of a novel endoplasmic reticulum (ER) DnaJ homologue, which stimulates ATPase activity of BiP in vitro and is induced by ER stress.
J. Biol. Chem.
277: 15947–15956.
- 121
Dorner, A.J.,
L.C. Wasley &
R.J. Kaufman. 1992. Overexpression of GRP78 mitigates stress induction of glucose regulated proteins and blocks secretion of selective proteins in Chinese hamster ovary cells.
EMBO J.
11: 1563–1571.
- 122
Bertolotti, A.
et al
. 2000. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response.
Nat. Cell. Biol.
2: 326–332.
- 123
Simons, K. &
D. Toomre. 2000. Lipid rafts and signal transduction.
Nat. Rev. Mol. Cell. Biol.
1: 31–39.
- 124
Nguyen, H.T.
et al
. 2006. Proteomic characterization of lipid rafts markers from the rat intestinal brush border.
Biochem. Biophys. Res. Commun.
342: 236–244.
- 125
Butchbach, M.E.
et al
. 2004. Association of excitatory amino acid transporters, especially EAAT2, with cholesterol-rich lipid raft microdomains: importance for excitatory amino acid transporter localization and function.
J. Biol. Chem.
279: 34388–34396.
- 126
Eroglu, C.
et al
. 2003. Glutamate-binding affinity of Drosophila metabotropic glutamate receptor is modulated by association with lipid rafts.
Proc. Natl. Acad. Sci. USA
100: 10219–10224.
- 127
Hering, H.,
C.C. Lin &
M. Sheng. 2003. Lipid rafts in the maintenance of synapses, dendritic spines, and surface AMPA receptor stability.
J. Neurosci.
23: 3262–3271.
- 128
Schrattenholz, A. &
V. Soskic. 2006. NMDA receptors are not alone: dynamic regulation of NMDA receptor structure and function by neuregulins and transient cholesterol-rich membrane domains leads to disease-specific nuances of glutamate-signalling.
Curr. Top Med. Chem.
6: 663–686.
- 129
Porter, R.H.
et al
. 1994. Polysynaptic regulation of glutamate receptors and mitochondrial enzyme activities in the basal ganglia of rats with unilateral dopamine depletion.
J. Neurosci.
14: 7192–7199.
- 130
Vila, M.
et al
. 1996. Metabolic activity of the basal ganglia in parkinsonian syndromes in human and non-human primates: a cytochrome oxidase histochemistry study.
NeuroScience
71: 903–912.
- 131
Wong-Riley, M. &
E.W. Carroll. 1984. Effect of impulse blockage on cytochrome oxidase activity in monkey visual system.
Nature
307: 262–264.
- 132
Nikonova, E.V.
et al
. 2005. Differences in activity of cytochrome C oxidase in brain between sleep and wakefulness.
Sleep
28: 21–27.
- 133
Mehrabian, Z.
et al
. 2005. Regulation of mitochondrial gene expression by energy demand in neural cells.
J. Neurochem.
93: 850–860.
- 134
Franken, P.,
D. Chollet &
M. Tafti. 2001. The homeostatic regulation of sleep need is under genetic control.
J. Neurosci.
21: 2610–2621.
- 135
Mackiewicz, M.
et al
. 2007. An silico analysis of genes in the QTL for sleep homeostasis in mice.
Physiol. Genomics.
- 136
Brakeman, P.R.
et al
. 1997. Homer: a protein that selectively binds metabotropic glutamate receptors.
Nature
386: 284–288.
- 137
Ango, F.
et al
. 2001. Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer.
Nature
411: 962–965.
- 138
Shiraishi-Yamaguchi, Y. &
T. Furuichi. 2007. The Homer family proteins.
Genome Biol.
8: 206.
- 139
Kato, A.
et al
. 1998. Novel members of the Vesl/Homer family of PDZ proteins that bind metabotropic glutamate receptors.
J. Biol. Chem.
273: 23969–23975.
- 140
Sato, M.,
K. Suzuki &
S. Nakanishi. 2001. NMDA receptor stimulation and brain-derived neurotrophic factor upregulate homer 1a mRNA via the mitogen-activated protein kinase cascade in cultured cerebellar granule cells.
J. Neurosci.
21: 3797–3805.
- 141
Xiao, B.
et al
. 1998. Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins.
Neuron.
21: 707–716.
- 142
Nelson, S.E.
et al
. 2004. Homer1a and 1bc levels in the rat somatosensory cortex vary with the time of day and sleep loss.
Neurosci. Lett.
367: 105–108.
- 143
Mackiewicz, M.
et al.
2008. Analysis of the QTL for sleep homeostasis in mice: Homer1a is a likely candidate.
Physiol. Genomics
33: 91–99.
- 144
Maret, S.
et al.
2007. Homer1a is a core brain molecular correlate of sleep loss.
Proc. Natl. Acad. Sci. USA
104: 20090–20095.
