- Email: [email protected]
Glia, Adenosine, and Sleep
Neuron
Previews Glia, Adenosine, and Sleep Barbara E. Jones1,* 1Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada *Correspondence: [email protected] DOI 10.1016/j.neuron.2009.01.005
Sleep is regulated by a homeostatic process that has long been thought to involve adenosine (AD) originating from neurons. In this issue of Neuron, Halassa et al. present evidence that sleep homeostasis depends upon gliotransmission and associated accumulation of AD that dampens neuronal excitability. Whereas glia were once thought to be by microdialysis, AD concentrations following hydrolysis of ATP released from passive structural elements in the brain, increase progressively in the brain with synaptic vesicles, as occurs along with they have more recently been revealed to prolonged waking and sleep deprivation most neurotransmitters, including Glu. An article published in this issue of be active players in providing metabolic and decrease progressively during sleep support for and regulating activity of the and sleep recovery (see for review Bash- Neuron by Halassa et al. (2009) opens an neurons they surround. Notably, it was eer et al., 2004), such as to suggest entirely new avenue in the study of the discovered that glia can be activated by a homeostatic control. AD was thought to cellular basis of sleep homeostasis and neurotransmitters released from adjacent accumulate in the extracellular space as role of AD. They examine the role of glioexcitatory synapses and can in turn a function of neural activity, either transmission and the importance of AD release chemical transmitters to act back following its equilibrative transport from released by astrocytes in sleep drive and upon those neurons through gliotransmis- nerve terminals, where it would increase homeostasis. They employ inducible sion (Figure 1) (Haydon and Carmignoto, with increased utilization of ATP and/or transgenic mice that express a dominant-negative (dn) SNARE domain 2006). The primary chemicals selectively in astrocytes and thus released from astrocytes are glutahave impaired gliotransmission. mate (Glu) and ATP, which can act Haydon and his colleagues had to facilitate neural transmission previously found in hippocampal (not shown). Yet, ATP is also slices that heterosynaptic depresrapidly hydrolyzed by ectonucleosion elicited by synaptic excitation tidase enzymes to adenosine is absent in dnSNARE transgenic (AD), which accumulates in the mice, is prevented in wild-type extracellular space and can act mice by AD antagonists, and is upon adenosine 1 receptors (A1R) on local neurons to tonically restored by AD agonists in the depress synaptic activity. This transgenic mice, thus suggesting neuron-glia-neuron feedback rethat this synaptic modulation is sults in activity-dependent attenumediated by AD hydrolyzed from ation of neural excitability, which ATP that is released by a vesicular could be relevant for sleep and its mode from the astrocytes (Pascual homeostatic regulation. et al., 2005) (see Figure 1). In the AD has long been thought to play current study, Halassa et al. exama role in sleep since caffeine, the ined whether sleep drive and major stimulant used around the homeostasis would be impaired Figure 1. Astrocytes Respond to and Dampen Activity in world, was found to act as an in the dnSNARE transgenic mice. Neighboring Excitatory Synapses by Gliotransmission antagonist at AD receptors. AD Indeed, they report a decrease in Glutamate (Glu) released from a presynaptic nerve terminal and binding to postsynaptic AMPA receptors (AMPAR) also diffuses antagonists increase waking and slow wave activity in the EEG beyond the synapse to act upon adjacent astrocytic processes decrease sleep along with EEG during sleep following waking and via metabotropic glutamate receptors (mGluR) and stimulate an slow wave activity in humans and thus a decrease in what is thought increase in intracellular calcium (Ca2+). ATP is released from actirodents (see for review Basheer to represent sleep pressure in the vated astrocytes in part from vesicles and is rapidly hydrolyzed to adenosine (AD). Through adenosine 1 receptors (A1R), AD et al., 2004; Benington and Heller, sleep-wake cycle. They then depresses Glu release from the presynaptic nerve terminal and 1995; Landolt, 2008). Conversely, show a loss of the compensatory hyperpolarizes the membrane of the postsynaptic neuron by AD and its analogs increase sleep response to sleep deprivation in blocking Ca2+ channels and increasing K+ conductance, thus effecting activity-dependent dampening of neuronal excitability. and enhance slow wave activity in the dnSNARE transgenic mice The accumulation of AD with prolonged neural activity could a way suggesting that AD could marked by a diminished enhancethereby contribute to sleep drive after waking and to cognitive defiserve as an endogenous sleep ment of slow wave activity and cits after sleep deprivation. Adapted with permission from (Haydon and Carmignoto, 2006). promoting substance. Measured increase in sleep amount, which
156 Neuron 61, January 29, 2009 ª2009 Elsevier Inc.
Neuron
Previews occur in wild-type mice. They moreover show a lack of cognitive impairment in the dnSNARE mice compared to wildtype mice on a novel object recognition task following sleep deprivation. The sleep homeostatic changes in EEG activity and associated cognitive deficits could be prevented in wild-type mice, and not affected in the dnSNARE transgenic mice, by A1R antagonists, suggesting that the sleep pressure, recovery, and cognitive deficits are due to AD and its action upon the A1R. The study thus dramatically demonstrates the importance of gliotransmission and the glia-dependent accumulation of AD for sleep drive and homeostasis. This study brings a new perspective to the understanding of sleep homeostasis, which can nonetheless accommodate many principles previously established for this process. First, it shows how gliotransmission can play a central role in sleep pressure by release of ATP leading to accumulation of AD in an activity-dependent manner. Second, it provides a substrate through which global but also local use-dependent changes can occur in AD accumulation and thus slow wave activity (Krueger et al., 2008), since astrocytes have limited territories of neurons
and synapses with which they are linked (see Haydon and Carmignoto, 2006). Third, it reveals a neuron-glia-neuron interaction to be involved in the homeostatic regulation of cortical slow wave activity, which has also been shown to be influenced or even paced through the same interaction (Amzica and Steriade, 2000). Questions to be examined in the future include whether the time course of AD accumulation and A1R activation fits the prolonged increase in slow wave activity and sleep following prolonged waking periods. What is the role in the AD accumulation of adenosine deaminase, the catabolic enzyme for which a genetic polymorphism is associated in humans with a propensity for sleepiness (Landolt, 2008)? Is ATP coreleased with Glu from astrocytes as it is from neurons, and would ATP and Glu not also play a role in potential glia-neuron synchronization by coordinated fast excitation on a background of slow AD-mediated hyperpolarization and resulting de-inactivation of T-type Ca2+ channels, which play a key role in thalamo-cortical slow wave oscillations (Crunelli et al., 2002)? Indeed, glia can release multiple factors that can contribute to sleep with slow wave activity
and to the restorative processes that must underlie sleep homeostasis (Krueger et al., 2008). REFERENCES Amzica, F., and Steriade, M. (2000). J. Neurosci. 20, 6648–6665. Basheer, R., Strecker, R.E., Thakkar, M.M., and McCarley, R.W. (2004). Prog. Neurobiol. 73, 379–396. Benington, J.H., and Heller, H.C. (1995). Prog. Neurobiol. 45, 347–360. Crunelli, V., Blethyn, K.L., Cope, D.W., Hughes, S.W., Parri, H.R., Turner, J.P., Toth, T.I., and Williams, S.R. (2002). Philos. Trans. R. Soc. Lond. B Biol. Sci. 357, 1675–1693. Halassa, M.M., Florian, C., Fellin, T., Munoz, J.R., Lee, S.-Y., Abel, T., Haydon, P.G., and Frank, M.G. (2009). Neuron 61, this issue, 213–219. Haydon, P.G., and Carmignoto, G. (2006). Physiol. Rev. 86, 1009–1031. Krueger, J.M., Rector, D.M., Roy, S., Van Dongen, H.P., Belenky, G., and Panksepp, J. (2008). Nat. Rev. Neurosci. 9, 910–919. Landolt, H.P. (2008). Biochem. Pharmacol. 75, 2070–2079. Pascual, O., Casper, K.B., Kubera, C., Zhang, J., Revilla-Sanchez, R., Sul, J.Y., Takano, H., Moss, S.J., McCarthy, K., and Haydon, P.G. (2005). Science 310, 113–116.
Silent Synapses Sit and Wait for a Better Day Darwin K. Berg1,* 1Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0357, USA *Correspondence: [email protected] DOI 10.1016/j.neuron.2009.01.004
Synaptic activity is thought to be critical for synaptic stabilization. In this issue of Neuron, Krishnaswamy and Cooper show that nicotinic synapses on autonomic neurons remain intact without synaptic activity. Postsynaptic responses are required, however, for presynaptic terminals to acquire the high-affinity choline transporter necessary for high-frequency transmission. Synapse formation involves both activitydependent and -independent steps. This was demonstrated early on at the vertebrate neuromuscular junction (NMJ), where cell adhesion molecules and diffusible factors guide many aspects of synapse formation between the motoneuron nerve terminal and the muscle fiber
(Sanes and Lichtman, 2001). Nerveinduced muscle activity via the transmitter acetylcholine (ACh) shapes later steps, including the removal of nonsynaptic nicotinic acetylcholine receptors (nAChRs) from the muscle fiber (Lomo and Rosenthal, 1972). Activity also provides the competition that reduces polyinnervation
to single synapses on mature muscle fibers (Lichtman and Colman, 2000). Excitatory synapses in the central nervous system differ dramatically from the NMJ in terms of size (much smaller), structure (presynaptic bouton/postsynaptic spine), and transmitter (glutamate), but they share the principle of activity-
Neuron 61, January 29, 2009 ª2009 Elsevier Inc. 157
Previews Glia, Adenosine, and Sleep Barbara E. Jones1,* 1Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada *Correspondence: [email protected] DOI 10.1016/j.neuron.2009.01.005
Sleep is regulated by a homeostatic process that has long been thought to involve adenosine (AD) originating from neurons. In this issue of Neuron, Halassa et al. present evidence that sleep homeostasis depends upon gliotransmission and associated accumulation of AD that dampens neuronal excitability. Whereas glia were once thought to be by microdialysis, AD concentrations following hydrolysis of ATP released from passive structural elements in the brain, increase progressively in the brain with synaptic vesicles, as occurs along with they have more recently been revealed to prolonged waking and sleep deprivation most neurotransmitters, including Glu. An article published in this issue of be active players in providing metabolic and decrease progressively during sleep support for and regulating activity of the and sleep recovery (see for review Bash- Neuron by Halassa et al. (2009) opens an neurons they surround. Notably, it was eer et al., 2004), such as to suggest entirely new avenue in the study of the discovered that glia can be activated by a homeostatic control. AD was thought to cellular basis of sleep homeostasis and neurotransmitters released from adjacent accumulate in the extracellular space as role of AD. They examine the role of glioexcitatory synapses and can in turn a function of neural activity, either transmission and the importance of AD release chemical transmitters to act back following its equilibrative transport from released by astrocytes in sleep drive and upon those neurons through gliotransmis- nerve terminals, where it would increase homeostasis. They employ inducible sion (Figure 1) (Haydon and Carmignoto, with increased utilization of ATP and/or transgenic mice that express a dominant-negative (dn) SNARE domain 2006). The primary chemicals selectively in astrocytes and thus released from astrocytes are glutahave impaired gliotransmission. mate (Glu) and ATP, which can act Haydon and his colleagues had to facilitate neural transmission previously found in hippocampal (not shown). Yet, ATP is also slices that heterosynaptic depresrapidly hydrolyzed by ectonucleosion elicited by synaptic excitation tidase enzymes to adenosine is absent in dnSNARE transgenic (AD), which accumulates in the mice, is prevented in wild-type extracellular space and can act mice by AD antagonists, and is upon adenosine 1 receptors (A1R) on local neurons to tonically restored by AD agonists in the depress synaptic activity. This transgenic mice, thus suggesting neuron-glia-neuron feedback rethat this synaptic modulation is sults in activity-dependent attenumediated by AD hydrolyzed from ation of neural excitability, which ATP that is released by a vesicular could be relevant for sleep and its mode from the astrocytes (Pascual homeostatic regulation. et al., 2005) (see Figure 1). In the AD has long been thought to play current study, Halassa et al. exama role in sleep since caffeine, the ined whether sleep drive and major stimulant used around the homeostasis would be impaired Figure 1. Astrocytes Respond to and Dampen Activity in world, was found to act as an in the dnSNARE transgenic mice. Neighboring Excitatory Synapses by Gliotransmission antagonist at AD receptors. AD Indeed, they report a decrease in Glutamate (Glu) released from a presynaptic nerve terminal and binding to postsynaptic AMPA receptors (AMPAR) also diffuses antagonists increase waking and slow wave activity in the EEG beyond the synapse to act upon adjacent astrocytic processes decrease sleep along with EEG during sleep following waking and via metabotropic glutamate receptors (mGluR) and stimulate an slow wave activity in humans and thus a decrease in what is thought increase in intracellular calcium (Ca2+). ATP is released from actirodents (see for review Basheer to represent sleep pressure in the vated astrocytes in part from vesicles and is rapidly hydrolyzed to adenosine (AD). Through adenosine 1 receptors (A1R), AD et al., 2004; Benington and Heller, sleep-wake cycle. They then depresses Glu release from the presynaptic nerve terminal and 1995; Landolt, 2008). Conversely, show a loss of the compensatory hyperpolarizes the membrane of the postsynaptic neuron by AD and its analogs increase sleep response to sleep deprivation in blocking Ca2+ channels and increasing K+ conductance, thus effecting activity-dependent dampening of neuronal excitability. and enhance slow wave activity in the dnSNARE transgenic mice The accumulation of AD with prolonged neural activity could a way suggesting that AD could marked by a diminished enhancethereby contribute to sleep drive after waking and to cognitive defiserve as an endogenous sleep ment of slow wave activity and cits after sleep deprivation. Adapted with permission from (Haydon and Carmignoto, 2006). promoting substance. Measured increase in sleep amount, which
156 Neuron 61, January 29, 2009 ª2009 Elsevier Inc.
Neuron
Previews occur in wild-type mice. They moreover show a lack of cognitive impairment in the dnSNARE mice compared to wildtype mice on a novel object recognition task following sleep deprivation. The sleep homeostatic changes in EEG activity and associated cognitive deficits could be prevented in wild-type mice, and not affected in the dnSNARE transgenic mice, by A1R antagonists, suggesting that the sleep pressure, recovery, and cognitive deficits are due to AD and its action upon the A1R. The study thus dramatically demonstrates the importance of gliotransmission and the glia-dependent accumulation of AD for sleep drive and homeostasis. This study brings a new perspective to the understanding of sleep homeostasis, which can nonetheless accommodate many principles previously established for this process. First, it shows how gliotransmission can play a central role in sleep pressure by release of ATP leading to accumulation of AD in an activity-dependent manner. Second, it provides a substrate through which global but also local use-dependent changes can occur in AD accumulation and thus slow wave activity (Krueger et al., 2008), since astrocytes have limited territories of neurons
and synapses with which they are linked (see Haydon and Carmignoto, 2006). Third, it reveals a neuron-glia-neuron interaction to be involved in the homeostatic regulation of cortical slow wave activity, which has also been shown to be influenced or even paced through the same interaction (Amzica and Steriade, 2000). Questions to be examined in the future include whether the time course of AD accumulation and A1R activation fits the prolonged increase in slow wave activity and sleep following prolonged waking periods. What is the role in the AD accumulation of adenosine deaminase, the catabolic enzyme for which a genetic polymorphism is associated in humans with a propensity for sleepiness (Landolt, 2008)? Is ATP coreleased with Glu from astrocytes as it is from neurons, and would ATP and Glu not also play a role in potential glia-neuron synchronization by coordinated fast excitation on a background of slow AD-mediated hyperpolarization and resulting de-inactivation of T-type Ca2+ channels, which play a key role in thalamo-cortical slow wave oscillations (Crunelli et al., 2002)? Indeed, glia can release multiple factors that can contribute to sleep with slow wave activity
and to the restorative processes that must underlie sleep homeostasis (Krueger et al., 2008). REFERENCES Amzica, F., and Steriade, M. (2000). J. Neurosci. 20, 6648–6665. Basheer, R., Strecker, R.E., Thakkar, M.M., and McCarley, R.W. (2004). Prog. Neurobiol. 73, 379–396. Benington, J.H., and Heller, H.C. (1995). Prog. Neurobiol. 45, 347–360. Crunelli, V., Blethyn, K.L., Cope, D.W., Hughes, S.W., Parri, H.R., Turner, J.P., Toth, T.I., and Williams, S.R. (2002). Philos. Trans. R. Soc. Lond. B Biol. Sci. 357, 1675–1693. Halassa, M.M., Florian, C., Fellin, T., Munoz, J.R., Lee, S.-Y., Abel, T., Haydon, P.G., and Frank, M.G. (2009). Neuron 61, this issue, 213–219. Haydon, P.G., and Carmignoto, G. (2006). Physiol. Rev. 86, 1009–1031. Krueger, J.M., Rector, D.M., Roy, S., Van Dongen, H.P., Belenky, G., and Panksepp, J. (2008). Nat. Rev. Neurosci. 9, 910–919. Landolt, H.P. (2008). Biochem. Pharmacol. 75, 2070–2079. Pascual, O., Casper, K.B., Kubera, C., Zhang, J., Revilla-Sanchez, R., Sul, J.Y., Takano, H., Moss, S.J., McCarthy, K., and Haydon, P.G. (2005). Science 310, 113–116.
Silent Synapses Sit and Wait for a Better Day Darwin K. Berg1,* 1Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0357, USA *Correspondence: [email protected] DOI 10.1016/j.neuron.2009.01.004
Synaptic activity is thought to be critical for synaptic stabilization. In this issue of Neuron, Krishnaswamy and Cooper show that nicotinic synapses on autonomic neurons remain intact without synaptic activity. Postsynaptic responses are required, however, for presynaptic terminals to acquire the high-affinity choline transporter necessary for high-frequency transmission. Synapse formation involves both activitydependent and -independent steps. This was demonstrated early on at the vertebrate neuromuscular junction (NMJ), where cell adhesion molecules and diffusible factors guide many aspects of synapse formation between the motoneuron nerve terminal and the muscle fiber
(Sanes and Lichtman, 2001). Nerveinduced muscle activity via the transmitter acetylcholine (ACh) shapes later steps, including the removal of nonsynaptic nicotinic acetylcholine receptors (nAChRs) from the muscle fiber (Lomo and Rosenthal, 1972). Activity also provides the competition that reduces polyinnervation
to single synapses on mature muscle fibers (Lichtman and Colman, 2000). Excitatory synapses in the central nervous system differ dramatically from the NMJ in terms of size (much smaller), structure (presynaptic bouton/postsynaptic spine), and transmitter (glutamate), but they share the principle of activity-
Neuron 61, January 29, 2009 ª2009 Elsevier Inc. 157