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Fast and slow Ca2+-dependent hyperpolarizationmechanisms connect
membrane potential and sleephomeostasisKoji L Ode1,2, Takahiro
Katsumata1, Daisuke Tone1 andHiroki R Ueda1,2
Available online at www.sciencedirect.com
ScienceDirect
Several lines of evidence indicate that the sleep-wake state
of
cortical neurons is regulated not only through neuronal
projections from the lower brain, but also through the
cortical
neurons’ intrinsic ability to initiate a slow firing pattern
related to
the slow-wave oscillation observed in electroencephalography
of the sleeping brain. Theoretical modeling and experiments
with genetic and pharmacological perturbation suggest that
ion
channels and kinases acting downstream of calcium signaling
regulate the cortical-membrane potential and sleep duration.
In
this review, we introduce possible Ca2+-dependent
hyperpolarization mechanisms in cortical neurons, in which
Ca2
+ signaling associated with neuronal excitation evokes
kinase
cascades, and the activated kinases modify ion channels or
pumps to regulate the cortical sleep/wake firing mode.
Addresses1Department of Systems Pharmacology, Graduate School of
Medicine,
The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo
113-0033,
Japan2 Laboratory for Synthetic Biology, RIKEN Quantitative
Biology Center,
1-3 Yamadaoka, Suita, Osaka 565-0871, Japan
Corresponding author: Ueda, Hiroki R ([email protected])
Current Opinion in Neurobiology 2017, 44:212–221
This review comes from a themed issue on Neurobiology of
sleep
Edited by Yang Dan and Thomas Kilduff
http://dx.doi.org/10.1016/j.conb.2017.05.007
0959-4388/ã 2017 Elsevier Ltd. All rights reserved.
IntroductionSleep is a fundamental brain state that is observed
across awide range of animal species [1,2]. Despite differences
incentral nervous system architecture, essential propertiesof sleep
appear to be broadly conserved across species.Sleep is a reversible
and homeostatically regulated stateof reduced responsivity to
environmental stimuli.Although the physiological functions of sleep
have notbeen fully explored, memory consolidation and
otherpotential roles of sleep appear to be highly conservedfrom
flies to humans [3]. This functional conservation
Current Opinion in Neurobiology 2017, 44:212–221
suggests that at least some of the mechanisms that regu-late
sleep are closely related to the fundamental proper-ties of neurons
in addition to the neural-circuit architec-ture specific to each
animal species.
Sleep-wake behavior is apparently controlled by systemsoperating
in a variety of time scales [4,5]. In the behav-ioral response, the
transition from wakefulness to sleepoccurs within a minute. In this
sense, the system thatswitches the entire brain (or at least most
of the corticalregions) to a sleep state may operate in a time
window ofseconds. Once animals fall asleep, the sleep state
con-tinues for hours in great apes (e.g., humans) or for a
fewminutes in most animals, including rodents (e.g., mice).Thus, a
system designed to measure the length of a sleepepisode would
operate on a time scale of minutes to hours.Furthermore, sleep is
homeostatically regulated on a timescale of a few days: sleep
deprivation on one day increasessleep pressure over the next few
days.
What kind of mechanism can control processes with sucha wide
range of time scales to control sleep, and beevolutionarily
conserved in so many species? In thisreview, we discuss the role of
calcium-ion (Ca2+) signalingin cortical neurons as a sleep
regulator. Ca2+ is a crucialfactor in regulating neuronal
properties across differenttime scales, from milliseconds to hours,
in different typesof neurons [6]. On a millisecond time scale, an
ion flux ofCa2+ directly depolarizes the membrane potential.
Aninflux of Ca2+ also triggers neurotransmitter release atthe
synapse [7]. Intracellular Ca2+ further induces severalmolecular
cascades that modulate neuronal propertiesover a longer time scale
(nearly an hour), such as theformation of synapses [8]. Thus, the
evolutionarily con-served and temporally diverse roles of Ca2+
signaling mayhave essential functions in sleep regulation. In
addition,we introduce the concept of Ca2+-dependent
hyperpolar-ization of the neuronal membrane potential during
sleep,which provides further mechanistic and quantitativeinsights
connecting sleep and Ca2+ signaling.
Ca2+-dependent hyperpolarization of cortical-membrane potential
during non-rapid eyemovement (NREM) sleepTransitions between wake
and sleep states are accompa-nied by qualitative alterations in
global neuronal firingpatterns in the cortex, which appear as
changes in
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Fast and slow Ca2+-dependent hyperpolarization mechanisms
connect membrane potential and sleep homeostasis Ode et al. 213
electroencephalogram (EEG) patterns. In the sleep
state,specifically, in non-rapid eye movement (NREM) sleep,the
synchronous firing of cortical neurons produces anEEG pattern with
a high amplitude and a low frequency,typically 0.5–4 Hz. The firing
pattern becomes non-syn-chronous when animals go into rapid eye
movement(REM) sleep or wake up; these states are characterizedby an
EEG pattern with a low amplitude and a highfrequency, and the
macroscopic firing pattern loses syn-chrony as individual cortical
neurons process variousenvironmental inputs. The synchronous firing
of corticalneurons during NREM sleep has been observed
acrossvertebrates from humans to lizards [9��].
Intracellular and extracellular electrophysiologicalrecordings
have revealed that the EEG pattern duringNREM sleep is composed of
various types of cortical-neuron activities: thalamocortical
neurons generateoscillations at 1–4 Hz, while cortical neurons
generateslow (
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214 Neurobiology of sleep
Figure 1
(a)
(b)
EEG recording
Wake NREM sleep
Cortical neuronal activity
EE
G a
mpl
itude
EE
G a
mpl
itude
Mem
bran
epo
tent
ial
Mem
bran
epo
tent
ial
NMDAreceptors
Voltage-gatedCa2+ channels
+ + +
- - -
+ +
- -
+ + +
- - -
Ca2+-activatedK+ channels
+ + +
- - -
+ +
- -
+ + +
- - -
Voltage-gatedK+ channels
Ca2+
K+
Depolarized up state Hyperpolarized down state
Mem
bran
epo
tent
ial
CalmodulinCurrent Opinion in Neurobiology
Regulation of cortical membrane potential during NREM sleep. (a)
Sleep/wake states are characterized by different behaviors of EEG
signals
originating from the collective activity of the cortical
neurons. Slow-wave EEG-signal oscillations during NREM sleep,
particularly those
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Fast and slow Ca2+-dependent hyperpolarization mechanisms
connect membrane potential and sleep homeostasis Ode et al. 215
Figure 2
State of cortical neuron-glia assembly
Sta
ble
Awake SleepSleepAwake
VLPOeVLPO
LCTMN
RapheVLPO
eVLPO
LCTMN
Raphe
Current Opinion in Neurobiology
Intrinsic ability of cortical cells to transition between
awake-firing and sleep-firing states. The cortical neuron–glia
assembly is thought to have two
stable states corresponding to an awake state and an NREM-sleep
state with a characteristic slow-wave oscillation pattern.
Wake-promoting and
sleep-promoting centers of the brain may stabilize the state of
cortical neurons, either in an awake or sleep state. VLPO:
ventrolateral preoptic
nucleus; eVLPO: extended ventrolateral preoptic nucleus; LC:
locus coeruleus; TMN: tuberomammillary nucleus.
bilateral-hemispheric sleep on land and unihemisphericsleep when
flying or swimming [23,24]. Based on thisview of sleep, researchers
have attempted to reconstructsleep in cultured neurons and glial
cells in vitro [25,26].Notably, Jewett et al. recapitulated the
homeostaticregulation of a sleep-like state in vitro: electrical
stimu-lation to induce a wake-like firing state in culturedneurons
was followed by an increase in the sleep-likefiring state on the
next day of stimulation, suggestingthat the cultured neuron itself
retains a homeostaticproperty that allows it to maintain constant
excitabilityover a day. Taken together, the cortex-intrinsic
changein state may provide a modified version of a flip-flopmodel:
regions of the brain, including the ventrolateralpreoptic nucleus
(VLPO) and other sleep/wake centers,induce a bias in the firing
state of the cortex, which itselfcan autonomically switch between
states of sleep andwakefulness (Figure 2).
If slow-wave oscillations in the cortex are producedautonomously
in the cortex, the next question is whethersuch an
electrophysiological pattern itself actively regu-lates sleep
duration in the entire organism. Massiminiet al. showed that using
5-Hz transcranial magnetic stim-ulation of the local cortex to
mimic the EEG pattern ofNREM sleep deepened slow-wave EEG activity
in asleeping human subject [27]. Thus, the state of the
localcortical neurons during sleep may actively control theanimals’
sleep. Several genetic studies support an activerole for the
cortical firing state; consistent with thecomputational prediction,
researchers successfully
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produced mice with longer or shorter sleep durationsby
manipulating the Ca2+-dependent hyperpolarizationpathway, which is
important for inducing a hyperpolar-ized silent phase. The
pharmacological inactivation orCRISPR/Cas9-mediated knockout of ion
channels toblock Ca2+ entry (i.e., NMDA receptors and
voltage-gatedCa2+ channels), along with the downstream
Ca2+-depen-dent K
+
channels, shortens the daily sleep duration inmice [19��,28�].
Given the critical roles of Ca2+ in generalneural function,
impairing Ca2+-dependent hyperpolari-zation pathways might produce
a non-specific phenotype(e.g., non-specific neural damage).
However, knocking outplasma-membrane Ca2+ ATPase (PMCA) genes to
inhibitCa2+ efflux lengthens sleep duration. Therefore, theopposing
sleep-duration phenotypes induced by inhibit-ing the Ca2+-dependent
hyperpolarization pathway or theCa2+-efflux pathway strongly
suggest that these effectsare not explained by a simple disruption
of the physio-logical controls.
The importance of cortical ion flux was furtherhighlighted by a
study that focused on the extracellularion environment. Ding et al.
found that natural sleep isassociated with a higher extracellular
Ca2+ and magne-sium ion (Mg2+) concentration and a lower
extracellularK+ concentration [29��]. This concentration bias
wouldsupport an influx of Ca2+ and efflux of K+. Consideringthat
astrocytes regulate the homeostasis of the extracel-lular ion
environment, the importance of extracellular ionconditions implies
the active involvement of not onlyneurons, but also glial cells for
inducing the sleep state.
Current Opinion in Neurobiology 2017, 44:212–221
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216 Neurobiology of sleep
Indeed, other studies have investigated how adenosinesignaling
through gliotransmission affects cortical slow-wave oscillations
[30] and promotes rebound sleep aftersleep deprivation [31].
Moreover, optogenetically stimu-lating astrocytes induces
synchronized slow-wave oscilla-tion in cortical neurons in vivo
[32�]. Thus, neuron–gliainteractions would act cooperatively to
modulate slow-wave oscillation patterns.
The cell-intrinsic properties that elicit slow-wave oscilla-tion
might be synchronized and organized through theneural-network
architecture. Studies using optogeneticsand designer receptors
exclusively activated by designer-drug (DREADD) perturbation
revealed a causal relation-ship between the sleep-wake transition
and the activity ofa subset of neurons. The core neuron subsets for
sleepregulation are in the basal forebrain for NREM control[33] and
in the pons/midbrain for REM control [34,35].These dedicated neural
circuits coordinate the state ofthe brain such that the state of
the entire organismswitches between sleep and wake states [36], and
lossof this coordination at the whole-brain level may lead tothe
abnormal EEG patterns associated with psychiatricdiseases
[37,38].
Slow dynamics: the homeostatic regulation ofsleep/wake cycles
through Ca2+-dependentphosphorylation cascadesThe close
relationship between membrane-potential con-trol and sleep-wake
dynamics presents a mystery as to themechanism that coordinates the
differences in time scalesbetween ion-flux regulation, which occurs
in the subse-cond order, and the regulation of sleep
homeostasis,which occurs over a period of hours. It is difficult
toaccount for the slow sleep dynamics based only on ion-flux
dynamics. A common biological architecture to pro-vide homeostatic
control over longer time scales is the useof signaling cascades.
Interestingly, the Ca2+-dependenthyperpolarization hypothesis of
sleep control proposesthat higher hyperpolarization activity (sleep
state) canbe triggered via Ca2+ influx by activating a
Ca2+-depen-dent pathway such as calcium/calmodulin-dependentkinase
II (CaMKII) a/b [19
��], which is important in
synaptic learning processes [39]. Knocking outCaMKIIa/b shortens
sleep duration, suggesting thatCaMKIIa/b play a role in inducing
sleep. The Ca2+-dependent hyperpolarization hypothesis proposes
thatactive neuron firing during an awake state causes an influxof
Ca2+, and a subsequent influx of CaMKIIa/b activatesa
Ca2+-dependent hyperpolarization mechanism toinduce NREM sleep
[19��].
Compared with the duration of a single episode of wake orsleep,
the dynamics of CaMKIIa/b activation itself uponneuronal excitation
are relatively fast—within a minute,at least at synapses [40]. This
time gap may be comple-mented by a kinase cascade downstream of
CaMKIIa/b.
Current Opinion in Neurobiology 2017, 44:212–221
Several studies on long-term potentiation (LTP) indicatethat
CaMKII further triggers the downstream mitogen-activated protein
kinases (MAPKs) ERK1/2, the activityof which is sustained for over
an hour [41,42]. Interest-ingly, a recent study demonstrated that
knocking outERK2 specifically in cortical neurons reduces
theNREM-sleep duration, and that the level of phosphory-lated
(active) MAPK differs between NREM and wakestates [43], although
other studies indicate that MAPKactivation is associated with REM
rather than NREM-sleep [44,45]. Ca2+ also potentiates PKC activity,
whichmay increase with sleep deprivation [46]. The activities
ofMAPK and PKC are altered by sleep-modulating sub-stances (D2
agonist, melatonin, and pentobarbital) [47].These results suggest
that the sleep-wake cycle affectsthe activity of kinases downstream
of Ca2+ signaling.
Another candidate kinase cascade downstream ofCaMKIIa/b was
recently identified by a forward geneticscreening of
sleep-controlling genes in mice [48��].NREM duration was
significantly longer in mice with asleepy mutation, which involves
exon skipping across theSIK3 kinase gene, with the loss of several
amino acidsincluding a PKA-phosphorylation site. This
phosphory-lation inhibits SIK3 activity, suggesting that the
sleepySIK3 mutant is a gain-of-function mutant. Sleep depriva-tion
did not appear to affect the level of
PKA-responsiblephosphorylation in SIK3. On the other hand, sleep
dep-rivation increased the SIK3-activating phosphorylationlevel;
thus, kinases other than PKA may be involved inthe sleep
deprivation-dependent phosphorylation ofSIK3.
The role of PKA in regulating sleep/wake cycles appearsto be the
opposite of that of CaMKIIa/b, SIK3, andERK1/2. For example, sleep
deprivation reducescAMP-PKA signaling in the hippocampus,
therebyimpairing memory consolidation [49–51]. Partially
sup-pressing PKA activity increased fragmentation and EEGdelta
power during NREM sleep [52]. Since the down-stream pathway of PKA
in sleep regulation is stillunknown, it will be interesting to
investigate the molec-ular interactions between sleep-promoting
kinases (e.g.,CaMKIIa/b, SIK3, and ERK1/2) and the awake-promot-ing
kinase PKA in the context of sleep/wake cycles.
Connecting fast and slow dynamics: Ca2+-dependent
phosphorylation cascadeshomeostatically regulate the
Ca2+-dependenthyperpolarization mechanismGenetic studies have
identified genes that regulate sleepduration, but the molecular
pathways that connect thesegenes are unknown. Sleep and sleep
deprivation canaffect numerous molecules such as ion channels,
pumps,and kinases both directly and indirectly. It is not enoughto
measure protein activity upon sleep deprivation (or thenatural
sleep-wake cycle) or to quantify sleep phenotypes
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Fast and slow Ca2+-dependent hyperpolarization mechanisms
connect membrane potential and sleep homeostasis Ode et al. 217
in animals with an impaired or enhanced activity of
geneproducts: to understand the molecular network of
sleepregulation, we need to illustrate a path from neuronalactivity
during the wake state to sleep-regulating factors.As a perspective
for future studies, we here discuss apossible signaling cascade
among sleep-regulating factors.Notably, the local power of the
slow-wave oscillation inthe cortex appears to respond to the
intensity of synaptictransmissions processed during the wake state
in the samelocal area [53–55], indicating that some part of the
mech-anism of sleep homeostasis is completed within the
localcortical area or even within the individual neurons.
Slow-wave oscillation is typically observed in NREMsleep, which
suggests that the ion channels involved inthis firing pattern act
differently during the NREM-sleepand wake states. Otherwise, an
influx of Ca2+ uponneuronal firing during the awake state would
suddenlyinduce Ca2+-dependent hyperpolarization, and the neu-ron
would not able to maintain an active awake state.Thus, it may be
reasonable to assume that during NREMsleep, (1) Ca2+ channels are
more permeable to Ca2+, (2)Ca2+-dependent K+ channels become more
sensitive andactive in response to Ca2+ influx, and/or (3) Ca2+
pumpsare less permeable to Ca2+. If the state of ion channels
andpumps is modified by highly excitable neuronal firing,then this
activity-dependent modification would close thehomeostatic loop:
prolonged wakefulness promotes sleep.The question, then, is how the
channels/pumps involvedare regulated. The mechanism that switches
corticalneurons between the awake and sleep states may involvethe
phosphorylation of ion channels or pumps. Althoughseveral studies
have investigated phospho-proteomicchanges in the sleep and awake
states [56], a criticalkinase substrate for homeostatic sleep
regulation hasyet to be identified. One simple hypothesis is
thatsleep-regulating kinases directly phosphorylate
sleep-regulating ion channels or pumps. To homeostaticallyinduce
sleep, kinases that are activated downstream ofincreased
excitability (e.g., accumulated Ca2+ signals) mayphosphorylate ion
channels or pumps to accelerate Ca2+-dependent hyperpolarization
(Figure 3). Thus, the Ca2+-dependent phosphorylation cascade may
form a slowCa2+-dependent hyperpolarization mechanism. Forexample,
the voltage-gated T-type Ca2+ channel CAC-NA1H (Cav3.2) is
activated when phosphorylated byCaMKII [57]. Considering that both
molecules promotesleep, based on the phenotypes of knockout mice,
andthat CaMKII is activated by synaptic input that is gener-ally
higher during the awake state, CaMKII might acti-vate CACNA1H to
promote wake-driven sleep. Identify-ing novel phosphorylation sites
will provide potentiallinks between sleep-regulating kinases and
substrates.Advances in mass spectrometry allow us to identify
phos-phorylation and other modifications comprehensivelyeven in
complex membrane proteins. Blesneac et al. tookthis approach with
CACNA1H [58] and identified tens of
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phosphorylation sites in vivo, some of which shifted thewindow
current of this channel to make it more sensitiveto
membrane-potential depolarization. As the amount ofmolecular
information increases, the next challenge is toevaluate which
molecular pathway is responsible forregulating sleep duration in
vivo.
The important feature of phosphorylation-dependentprotein
regulation is its reversibility. Thus, the impor-tance of kinases
in sleep regulation implies that theirreverse enzymes,
phosphatases, are also critical forregulation. Currently, no potent
sleep-related phospha-tases have been discovered in mammals;
however, nota-bly, phosphorylation can also be reversibly regulated
byproteolysis-synthesis protein turnover. In other words,the
degradation of old phosphorylated proteins and thesynthesis of new
proteins can supply unphosphorylatedproteins with an effect similar
to the dephosphorylationof phosphorylated proteins. Indeed, the
transcriptionfactor CREB, which is regulated by PKA, is involvedin
regulating sleep duration. Reducing CREB expres-sion sharply
increases the sleep time in mice [59], andthe CREB, PKA, and MAPK
activities change duringthe sleep-wake cycle [44]. In flies,
PKA–CREB activityis important for sleep particularly in the
mushroombody, a part of the brain that is critical for
regulatingsleep-wake behavior in the fly. As in mammals,
blockingthe CREB activity increases sleep in flies, [60] whilePKA
overexpression inhibits sleep [61]. These resultssuggest that
elevated cAMP signaling modulates CREBactivity to reduce the amount
of sleep. Alternatively,the protein degradation pathway is also
important forcontrolling sleep: a genetic study in flies identified
theshort-sleep insomniac gene, which encodes a proteinregulating
the Cullin-3 ubiquitin ligase complex [62].We also note that
ion-channel regulation at the tran-scription or translation level
has been implicated as anunderlying mechanism for periodic changes
in mem-brane excitability during day/night cycles in mice andflies
[63–65], and that some parts of the sleep/wakecycle may involve
periodic regulation at the transcrip-tion or translation level.
Sleep duration and structure depends markedly on
thedevelopmental stage [66], and the
Ca2+-dependenthyperpolarization pathway may be involved in
sleepregulation over the animal’s life span. The NMDA recep-tor
member Nr3a is known for its age-dependent expres-sion in rodents,
which peaks during a critical period ofexperience-dependent
synaptic plasticity [67,68]. TheNr3a expression is low in adult
rodents and humans.Notably, knocking out the Nr3a gene shortens
sleep,but knocking out the other non-lethal NMDA receptorgenes does
not (Nr2a, Nr2c, Nr2d, and Nr3a) [28�]. Nr3a’sunique
sleep-promoting role may be part of an underlyingmechanism to
ensure a higher amount of sleepduring childhood and a lower amount
after adolescence.
Current Opinion in Neurobiology 2017, 44:212–221
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218 Neurobiology of sleep
Figure 3
NMDAreceptors
Voltage-gatedCa2+ channels
Ca2+-activated K+ channels
Voltage-gatedK+ channels
K+
Ca2+
Wake-associated activation of kinase signaling cascade Induction
of up-state / down-state oscillation
Ca2+ channelsGPCRs
CaMKIIα/β (sleep promoting kinases)
PKA, PKC etc
SIK3 (a sleep promoting kinase)
Ca2+
ERK1/2 (sleep promoting kinases)
Current Opinion in Neurobiology
Possible relationship between sleep-regulating kinases, ion
channels and pumps, and the neuronal firing-dependent control of
membrane
potential. Several kinases are activated through Ca2+ influx and
other awake-associated signals. Kinases are slow-regulation factors
in the sleep-
wake cycle. The activated kinases modify ion channels involved
in the slow-wave oscillation pattern, and the ion channels act as
fast-regulation
factors. This connection between slow and fast regulation
factors provides a plausible mechanism for the homeostatic control
of wake-induced
sleepiness. GPCRs: G protein-coupled receptors.
Similarly, the expression of Cacna1g decreases in agedhumans
[69]. Knocking out Cacna1g shortens sleep dura-tion; thus,
decreased Cacna1g expression may decreasenighttime sleep duration
in the elderly.
Current Opinion in Neurobiology 2017, 44:212–221
Evolutionary conservation of cell-intrinsicsleep
regulationSeveral studies in flies show that ion-channel activities
aremodulated during the sleep-wake cycle. One study
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Fast and slow Ca2+-dependent hyperpolarization mechanisms
connect membrane potential and sleep homeostasis Ode et al. 219
showed that a reduction of voltage-gated K+ current(through
Shaker and Slab) and induction of leak K+ current(through Sandman)
form the underlying mechanism forthe dopamine-mediated
hyperpolarization of the dFB, asleep-promoting region of the brain
in flies [70]. Thisstudy also connected the roles of the classical
sleep-related mutants found in Fmn [71] and Shaker flies[72], and
demonstrated that the Shaker molecule itselfis dynamically
regulated by the sleep-wake cycle.Another study identified a set of
neurons responsiblefor sleep deprivation and subsequent rebound
sleep inflies [73��]; interestingly, sleep deprivation results in
anincrease in Ca2+ levels and NMDA receptors in thisneuron set. The
study further demonstrated that Ca2+
is released from ER storage through the IP3 receptor inresponse
to sleep deprivation. In a broad sense, mousegenetics focusing on
cortical excitability overlap with flygenetics in identifying key
players: intracellular Ca2+
signal, altered K+ current, and kinases/phosphatasespotentially
regulate channel properties [60,61,74–76].Although studies in flies
suggest that these ion channelsoperate mostly in a defined set of
sleep-regulating neu-rons, we would nonetheless point out that even
in flies,the excitability of individual neurons in response
tostimuli is reduced depending on the preceding awakeperiod [77�].
This finding is consistent with local sleep inmammals; thus,
neuron-intrinsic homeostasis may also bevalid in flies. Another fly
study showed that blocking theNMDA receptor decreases sleep, as was
also observed inmammals, and that pan-neurons (rather than a
specific setof neurons) appear to contribute to this effect [78��].
Inaddition, the Ca2+-dependent phosphatase calcineurinpromotes
sleep in the fruit fly [75,76]. The NMDAreceptor and Ca2+-dependent
phosphatase might actcooperatively rather than in opposition to
induce sleepin fruit flies.
ConclusionThe genetic identification of sleep-regulating genes
hasprovided a list of ion channels/pumps and kinases thatmay
function pan-neuronally. Connecting the enzyme-substrate networks
among these molecules may reveal acellular cascade that is
conserved across neuron subtypesand across phyla, in which case the
molecular pathwayshould be understood in the context of neural
networks.Revisiting the homeostatic action of mammalian sleep,sleep
deprivation increases the power of slow-wave activ-ity observed on
EEG. This effect might be due tochanges in the intraneuronal
molecular properties ofindividual cortical neurons and to
functional changes inthe neural circuits that synchronize the
cortical neuronstate; it is highly possible that both mechanisms
areimportant for brain function. To understand the mecha-nism of
sleep control in a complex neural network, webelieve that it is
necessary to understand the properties ofeach neuron during the
sleep-wake cycle, because the
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system behavior emerges from the properties of both
thearchitecture and the components.
Conflict of interest statementThe authors have no conflict of
interest regarding on thismanuscript.
AcknowledgementsThis work was supported by AMED-CREST, CREST,
Brain/MINDS, theBasic Science and Platform Technology Program for
Innovative BiologicalMedicine, JSPS (25221004, 23115006, 25830146,
16K14653), RIKEN, andthe Takeda Science Foundation.
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Fast and slow Ca2+-dependent hyperpolarization mechanisms
connect membrane potential and sleep
homeostasisIntroductionCa2+-dependent hyperpolarization of
cortical-membrane potential during non-rapid eye movement (NREM)
sleepFast dynamics: the Ca2+-dependent hyperpolarization mechanism
acts through ion channels and pumps during NREM sleepSlow dynamics:
the homeostatic regulation of sleep/wake cycles through
Ca2+-dependent phosphorylation cascadesConnecting fast and slow
dynamics: Ca2+-dependent phosphorylation cascades homeostatically
regulate the Ca2+-dependent hyp...Evolutionary conservation of
cell-intrinsic sleep regulationConclusionReferences and recommended
readingConflict of interest statementAcknowledgements