Sleep Deprivation Impairs cAMP Signaling in the Hippo Campus

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Nature. Author manuscript available in PMC 2010 April 22.Published in final edited form as:

Nature. 2009 October 22 461(7267): 11221125.doi: 10.1038/nature08488

PMCID: PMC2783639NIHMSID: NIHMS143282

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Sleep deprivation impairs cAMP signaling in the

hippocampus

Christopher G. Vecsey,1,2 George S. Baillie,3 Devan Jaganath,2 Robbert

Havekes,2 Andrew Daniels,2 Mathieu Wimmer,1,2 Ted Huang,1,2 Kim M.

Brown,3 Xiang Yao Li, 4 Giannina Descalzi,4 Susan S. Kim,4 Tao Chen,4Yu Ze Shang, 4 Min Zhuo,4 Miles D. Houslay,3 and Ted Abel2

1Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, PA, 191042Department of Biology, University of Pennsylvania, Philadelphia, PA, 191043Neuroscience and Molecular Pharmacology, Wolfson and Davidson Buildings, Faculty of Biomedical and Life

Sciences, University of Glasgow , Glasgow G12 8QQ, Scotland, UK4Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, CanadaAddress correspondence to: Ted Abel, Email: [email protected], Phone: (215) 898 3100, Fax: (215) 898

8780

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The publisher's final edited version of this article is available at NatureSee other ar ticles in PMC that cite the published article.

Abstract

Millions of people regularly obtain insufficient sleep1. Given the impact of sleep

deprivation on our lives, understanding the cellular and molecular pathways affected

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Vecsey, C.

Baillie, G.

Jaganath, D.

Abel, T.

Phosphodies terase 4D knock out and RNA interference

mediated knock down enhance memory and increase

[J Neurosci. 2011]

Ndel1 alters its conformation by sequestering cAMP specific

phosphodiesterase 4D3 (PDE4D3) in a manner that is

[Cell Signal. 2008]

Rolipram, a type IV specific phosphodiesterase inhibitor,

facilitates the es tablishment of long lasting long term

[Proc Natl Acad Sci U S A. 1998]

Review Regulation of hippocampa l synaptic plasticity by

cyclic AMP dependent protein ki nases. [Prog Neurobiol. 2003]

Review Signal ing from cAMP/PKA to MAPK and synaptic

plasticity. [Mol Neurobiol . 2003]

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Sleep deprivation impairs cAMP signal ing in the

hippocampus
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Other Sections

by sleep deprivation is clearly of social and clinical importance. One of the major

effects of sleep deprivation on the brain is to produce memory deficits in learning

paradigms that are dependent on the hippocampus25. In this study, we have

identified a molecular mechanism by which brief sleep deprivation alters

hippocampal function. Sleep deprivation selectively impaired cAMP/PKA dependent

forms of synaptic plasticity6 in the hippocampus, reduced cAMP signaling, and

increased activity and protein levels of phosphodiesterase 4 (PDE4), an enzyme that

degrades cAMP. Treatment with PDE inhibitors rescued the sleep deprivation

induced deficits in cAMP signaling, synaptic plasticity, and hippocampus dependent

memory. These findings demonstrate that brief sleep deprivation disrupts

hippocampal function by interfering with cAMP signaling through increased PDE4

activity. Thus drugs that enhance cAMP signaling may provide a novel therapeutic

approach to counteract the cognitive effects of sleep deprivation.

Keywords: sleep deprivation, mouse, hippocampus, memory, synaptic plasticity, cAMP,

phosphodiesterase, PDE4, PDE4A5, rolipram

To determine the cellular and molecular mechanisms by which a short 5 hour period

of sleep deprivation affects hippocampal function2, we used in vitro

electrophysiological recordings to examine the effects of sleep deprivation on

hippocampal long term potentiation (LTP), a form of synaptic plasticity that relies on

molecular mechanisms that are also important for memory consolidation7. We

examined several forms of NMDA receptor dependent LTP with different underlyingmolecular mechanisms to identify molecular targets of sleep deprivation. The long

term maintenance of LTP following spaced 4 train stimulation or theta burst

stimulation (TBS) depends on cyclic AMP (cAMP), protein kinase A (PKA),

transcription, and translation810. Both of these forms of LTP were impaired in

hippocampal slices from mice that had been deprived of sleep for 5 hours (Fig. 1ab

). The increased need for sleep that follows brief s leep deprivation dissipates in

approximately 2.5 hours11, and we found that the deficit in spaced 4 train LTP also

Compound

PubMed

Substance

See more articles cited in this paragraph

Sleep deprivation selectively impairs m emory consolidationfor contextual fear conditioning.

Review Synaptic plasticity and memory: an evaluation of the

hypothesis.

Recruitment of long lasting and protein kinase A dependentlong term potentiation in the CA1 region of hippocampus

Brief theta burst stimu lation induces a transcription dependent late phas e of LTP requiring cAMP in area CA1 of

Effects of sleep deprivation on s leep and s leep EEG in threemouse strains: empirical data and s imulations.

[Learn Mem. 2003]

[Annu Rev Neurosci. 2000]

[Learn Mem. 1994]

[Learn Mem. 1997]

[Brain Res. 2000]
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recovered with 2.5 hours of rest after 5 hours of sleep deprivation (Supplemental Fig.

S4). Massed 4 train LTP, which induces a stable form of LTP that depends on

translation12, but does not require cAMP/PKA signaling12,13, was unimpaired by

sleep deprivation (Fig. 1c). One train LTP, a cAMP/PKA independent form of LTP 6

was also unaffected by sleep deprivation (Fig. 1d). The lack of an effect of sleep

deprivation on massed 4 train LTP and 1 train LTP suggests that brief sleep

deprivation does not affect molecular mechanisms that are required for the induction

and expression of these forms of LTP, such as NMDA receptor activation, Ca2+ influx

and activation of Ca2+calmodulin dependent kinase II (CaMKII) 8,14,15. Because

massed 4 train requires translation, the fact that s leep deprivation does not affect this

form of LTP suggests that brief sleep deprivation does not generally disrupt

translational processes, but instead specifically alters mechanisms that depend upon

cAMP/PKA signaling. Whole cell recordings from area CA1 confirmed that NMDA

receptor function was unaffected by sleep deprivation (Supplemental Fig. S3). These

results contrast with studies using longer periods of sleep deprivation, or sleep

deprivation that involves exploration of a novel environment, both of which affect the

initial induction of LTP as well as NMDA receptor function4,1620. We also did not

observe any effects of sleep deprivation on basal synaptic properties or short term

plasticity (Supplemental Fig. S2), suggesting that the disruption of spaced 4 train and

theta burst LTP is in fact due to disruption of signaling mechanisms underlying these

forms of LTP and is not due to non specific effects on hippocampal function.

Figure 1

Brief sleep deprivation specifically impairs forms of LTP that depend

on the cAMP/PKA pathway

Because of the role of cAMP signaling in 4 train and theta burst LTP 8,13, we next

assessed the effects of sleep deprivation on LTP induced by specific activation of the

cAMP pathway using the adenylate cyclase activator forskolin. The long termRecruitment of long lasting and protein kinase A dependentlong term potentiation in the CA1 region of hippocampus

[Learn Mem. 1994]
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maintenance of LTP induced by treatment with forskolin (50M) was impaired in

hippocampal slices from sleep deprived mice ( Fig. 2a). Using biochemical assays,

we found that baseline cAMP levels were significantly reduced in the CA1 region of

hippocampal slices from sleep deprived mice, as were cAMP levels induced by

forskolin treatment (Fig. 2c). These findings demonstrate that s leep deprivation limits

the ability of cells within the CA1 region of the hippocampus to respond to adenylate

cyclase activation. Using immunohistochemistry, we found that phosphorylation at

Ser133 of CREB, one of the downstream targets of cAMP signaling in the

hippocampus21, was decreased by sleep deprivation in the CA1 and dentate gyrus

(DG) regions of the hippocampus (Supplemental Fig. S7). Consistent with our

published findings that brief sleep deprivation selectively impairs hippocampal

function2, no effect of sleep deprivation on CREB phosphorylation was observed in

the amygdala (Supplemental Fig. S7). This demonstrates that deficient cAMP

signaling due to sleep deprivation impairs the activation of at least one major

downstream target (CREB) in vivo. Cyclic nucleotide phosphodiesterases (PDEs)

are enzymes that provide the sole route for cAMP degradation in cells22. We foundthat co treatment with IBMX (30M), a broad spectrum inhibitor of PDEs, rescued

forskolin induced LTP as well as cAMP induction in hippocampal slices from sleep

deprived mice (Fig. 2bc). These findings demonstrate that reversing deficits in

cAMP signaling ameliorates the deficits in forskolin induced LTP, and suggest that

PDE activity might be increased by s leep deprivation.

Figure 2

Phosphodiesterase (PDE) inhibition rescues impairments in forskolin induced cAMP levels and LTP produced by brief sleep deprivation

cAMP specific PDE4 has a major role in regulating cAMP signaling in the brain 22.

Therefore, we tested if sleep deprivation increased PDE4 levels and/or activity in the

hippocampus. We found that PDE4 specific cAMP breakdown was increased in SD

Temporal spacing of synaptic stimula tion criticallymodulates the dependence of LTP on cyclic AMP dependent

Review CREB, synapses and memory disorders: past

progress and future challenges.

Sleep deprivation selectively impairs m emory consolidationfor contextual fear conditioning.

Review PDE4 cAMP phosphod iesterases : modular

enzymes that orchestrate signalling cross talk,



[Hippocampus. 2003]

[Curr Drug Targets CNS Neurol Disord. 2005]

[Learn Mem. 2003]

[Biochem J. 2003]

[Biochem J. 2003]
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mice (Fig. 3a), whereas non PDE4 activity was unaffected (SD = 50.6 2.1

pmol/mg/min, NSD = 53.4 1.9 pmol/mg/min, p=0.33). In mice and humans, PDE4

isoforms are generated by four genes: PDE4A-D22. Immunoblotting with a pan

PDE4A antibody showed a trend in sleep deprived hippocampal tissue towards an

increase in a 125 kDa species, which is of a size expected for the long PDE4A5,

PDE4A10 and PDE4A11 isoforms23 (Supplemental Fig. S6). Probing our

hippocampal samples with antisera specific for each of these isoforms showed that

PDE4A5 protein was significantly increased by sleep deprivation in the hippocampus,

whereas PDE4A10 and PDE4A11 were not detected (Fig. 3b for PDE4A5 data not

shown for null results with PDE4A10, PDE4A11). Interestingly, transcripts for

PDE4A5 are selectively expressed in the brain with highest levels seen in

hippocampal areas CA1 and DG24, the two regions in which reduction in pCREB

were observed following sleep deprivation (Fig. S7). We also found that sleep

deprivation elicited upregulation of PDE4 gene expression, although the pattern of

changes was somewhat different between transcript and protein levels, suggesting

that translation regulation mechanisms may be involved (Supplemental Fig. S5).

Figure 3

Sleep deprivation increases PDE4 activity and gene expression in the

hippocampus

To test whether increased PDE4 activity is responsible for deficits in hippocampal

function induced by sleep deprivation, we first examined whether the PDE4 selective

inhibitor rolipram22 could rescue deficits in LTP induced by sleep deprivation. Indeed,

rolipram treatment (0.1M) during spaced 4 train stimulation rescued the

maintenance of this form of LTP in slices from sleep deprived mice. This dose of

Identification and characterization of PDE4A11, a novel,widely express ed long isoform encoded by the human

The novel long PDE4A10 cyclic AMP phosphodiesteraseshows a pattern of express ion within brain that is dis tinct



Review Keynote review: phosphodiesterase 4 as a

therapeutic target.

[Mol Pharmacol. 2005]

[Cell Signal. 2001]

[Biochem J. 2003]

[Drug Discov Today. 2005]
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rolipram had no effect on 4 train LTP in slices from control mice, suggesting that this

result was not simply due to a non specific enhancement of LTP ( Figs. 3a and 3b).

To rule out the possibility of a ceiling effect, we assessed the effects of rolipram in

slices from sleep deprived and control mice on 1 train LTP, which is normally a

transient form of plasticity. Here, rolipram enhanced the maintenance of 1 train LTP

in control mice. However, rolipram had no significant effect in sleep deprived mice,

demonstrating that sleep deprived mice have a reduced sensitivity to the effects of

PDE4 inhibition (Supplemental Fig. S8). These findings suggest that sleepdeprivation makes it more difficult to reach the threshold for induction of cAMP/PKA

dependent LTP, consistent with our observation that sleep deprivation increases the

activity of a specific PDE4 isoform that is known to set the threshold for activation

when recruited to specific signaling complexes25.

We next assessed whetherin vivo PDE4 inhibition could prevent impairments in

hippocampus dependent memory consolidation induced by post training sleep

deprivation. Immediately following single trial contextual fear conditioning, mice wereeither deprived of sleep by gentle handling for 5 hours or were left undisturbed in their

home cages. Mice received 2 IP injections of either rolipram (ROL 1 mg/kg) or

vehicle (VEH), immediately and 2.5 hours following training. The timing of these

injections was based on data showing that the effects of rolipram on hippocampal

cAMP levels last for about 3 hours (personal communication, Dr. James ODonnell).

Memory was assessed using a 5 minute retrieval test in the trained context 1 day

after conditioning and in an altered context 2 days after conditioning. Context specific

memory, a measure that is particularly dependent on hippocampal function

26

, wasmeasured by subtracting the percent freezing in the altered context from the percent

freezing in the trained context (see Supplemental Fig. S9 for data from these two

tests). Sleep deprivation significantly impaired context specific memory, and rolipram

treatment rescued this deficit (Fig. 4c). The ability of rolipram to rescue deficits in

hippocampus dependent memory produced by sleep deprivation demonstrates that

disruption of cAMP signaling is responsible for the effects of sleep deprivation in vivo.

The dorsal hippocampus is essential for context

discrim ination but not for contextual conditioning.[Behav Neurosci. 1998]
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Other Sections

Figure 4

The PDE4 inhibitor rolipram rescues LTP and memory deficits

caused by sleep deprivation

A major challenge in the field of sleep research has been to determine how the sleep

disruptions associated with neurological and psychiatric disorders, aging, andeveryday living affect cognitive function. These findings are the first to define a

molecular mechanism underlying the effects of sleep deprivation on hippocampal

function at the behavioral and synaptic level, and they lay the groundwork for further

analysis of the functional biochemistry of sleep deprivation and the development of

novel therapeutics to ameliorate the impact of sleep deprivation. These experiments

using the PDE4 inhibitor rolipram are the first to rescue synaptic plasticity and

memory deficits produced by a brief period of sleep deprivation. Our data suggest

that if compounds can be developed that block either the activity, expression, ortargeting of the PDE4A5 isoform, they may prove useful in the treatment of the

cognitive effects of sleep deprivation. Interestingly, circadian oscillation of cAMP in

the hippocampus has recently been linked to the persistence of memory27 so such

drugs may also be useful in treating memory deficits associated with alterations in

circadian rhythms. It has proven difficult to generate active site directed inhibitors

showing selectivity for each of the four PDE4 sub families because of the highly

conserved structure of their catalytic unit25, but it may be possible to develop

compounds that disrupt the targeting of specific PDE4 isoforms from appropriatescaffolds in cells22,25.

Methods Summary

C57BL/6J male mice (25 months of age) were housed individually on a 12 hr/12 hr

light/dark schedule with lights on at 7 A.M. (ZT0) and handled for 6 days. Mice were

sleep deprived (SD) in their home cages for 5 hours by gentle handling beginning at

Review Keynote review: phosphodiesterase 4 as a

therapeutic target.



[Drug Discov Today. 2005]

[Biochem J. 2003]
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ZT5 or left undisturbed (non sleep deprived mice, NSD). For contextual fear

conditioning experiments, animals were placed in a novel chamber for 3 minutes,

and received a 2 second, 1.5 mA footshock after 2.5 minutes. Half of the mice were

deprived of sleep for 5 hours post training. Mice received intra peritoneal injections of

rolipram (ROL 1 mg/kg) or vehicle (2% DMSO in 0.9% saline) immediately and 2.5

hours post training. Testing of contextual memory was performed 24 hours after

training in the trained context and 48 hours after training in a novel chamber.

Electrophysiological recordings were carried out as previously reported28. 1 train

LTP was induced by a single 100 Hz, 1 second duration train of stimuli. 4 train LTP

consisted of 4 trains applied with a 5 minute inter train interval for massed 4 train

LTP a 5 second inter train interval was used. Theta burst stimulation (TBS)

consisted of 40 ms duration, 100 Hz bursts delivered at 5 Hz for 3 seconds (15

bursts of 4 pulses per burst, for a total of 60 pulses). Chemical LTP was induced by

treatment of slices for 15 minutes with 5M forskolin (FSK) in 0.1% ethanol, or a

combination of 50M forskolin and 30M 3 isobutyl 1 methylxanthine (IBMX, in water).Rolipram (0.1M in 0.1% DMSO) was applied for 60 minutes, beginning 30 minutes

before tetanization.

cAMP assays on CA1 regions of hippocampal slices 10 minutes after treatment for

15 minutes with forskolin (50M), forskolin + IBMX (30M), or vehicle (0.1% EtOH)

were performed by radioimmunoassay according to kit instructions. cAMP specific

PDE activity assays29 and Western blots for PDE4A530 were performed as

previously described.

Full Methods and any associated references are available in the online version of

the paper at www.nature.com/nature.

Supplementary Material

1

Click here to view.(1.3M, pdf)

Histone deacetylase inhib itors enhance mem ory andsynaptic plas ticity via CREB:CBP dependent transcriptional

Identification of two splice variant forms of type IVB cyclicAMP phosphodies terase, DPD (rPDE IVB1) and PDE 4

The cAMP specific phosphodiesterase PDE4A5 is cleaveddownstream of its SH3 interaction domain by caspas e 3.

[J Neurosci. 2007]

[Biochem J. 1994]

[J Biol Chem. 2000]
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Acknowledgements

We thank Dr. Amita Sehgal and Joshua Hawk for their comments on the manuscript.

We thank Dr. James ODonnell for his help with planning rolipram treatment

experiments. We thank Dr. James Bibb for helpful discussions and comments on the

manuscript. We thank Dr. Steven Fluharty and Dr. Jon Lindstrom for the use of their

gamma scintillation counters, and Dr. Tracy Bale, Dr. Nirupa Goel, Dr. Kate Semsar,

and Dr. Sarah Teegarden for their help with corticosterone assays. We also thank

Dr. Pepe Hernandez, Nora Khatib, Alan Park, James Lederman, Dr. Cedrick Florian,

and Dr. Wei Lu for their help with experiments. This research was supported by

Systems and Integrative Biology Training Grant GM07517 (To C.G.V. M. Nusbaum

P.I.), NIH training grant HL07953 (to C.G.V. A.I. Pack P.I.), the Netherlands

Organization for Scientific Research NWO Rubicon Grant 825.07.029 (to R.H.), the

National Institutes of Health (AG017628) (to T.A. A.I. Pack, P.I.), SCOR Grant

HL060287 (to T.A., A.I. Pack, P.I.), HFSP grant RGSP/2005 (to T.A.), the Medical

Research Council (UK) grant G0600765 (to M.D.H. and G.S.B.), the European Union

grant LSHB CT 2006 037189 (to M.D.H.), the Fondation Leducq grant 06CVD02 (to

M.D.H. and G.S.B.), CIHR84256 (to M.Z.), and a UK Engineering and Physical

Sciences Research Council training grant (to K.M.B.).

Footnotes

Author Contributions

Experiments w ere conceived and designed by C.G.V., T.A., G.S.B., M.D.H., and M.Z. Behavioral and gene

expression experiments w ere carried out by D.J. and C.G.V. Electrophysiological recordings w ere carried out by

C.G.V. and T.H. cAMP assays w ere carr ied out by C.G.V. Western blots w ere carr ied out by K.M.B. PDE activity
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Other Sections

assays w ere carr ied out by G.S.B. Immunohistochemistry ex periments were carr ied out by R.H. and A.D.

EEG/EMG recordings w ere carr ied out by M.W. Sleep deprivation and electrophysiology for w hole cell patch

clamp recordings w ere performed by X. Y.L., G.D., S.S.K., T.C., and Y Z.S. Manuscript w as prepared by C.G.V.

and T.A., w ith input f rom D.J., R.H., M.W., G.S.B. and M.D.H.

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions .

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Sleep Deprivation Impairs cAMP Signaling in the Hippo Campus

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