Astrocyte Action In Sleep

Neuron

Report
Astrocytic Modulation of Sleep Homeostasis and Cognitive Consequences of Sleep Loss
Michael M. Halassa,1,3 Cedrick Florian,2 Tommaso Fellin,1,4 James R. Munoz,1 So-Young Lee,1,3 Ted Abel,2 Philip G. Haydon,1,3,5,* and Marcos G. Frank1,5
of Neuroscience of Biology University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA 3Department of Neuroscience, TuftsUniversity Schools of Medicine, Boston, MA 02111, USA 4Present address: Italian Institute of Technology, via Morego 30, 16163 Genova, Italy 5These authors contributed equally to this work *Correspondence: philip.haydon@tufts.edu DOI 10.1016/j.neuron.2008.11.024
2Department 1Department

SUMMARY

Astrocytes modulate neuronal activity by releasing chemical transmitters via a process termedgliotransmission. The role of this process in the control of behavior is unknown. Since one outcome of SNARE-dependent gliotransmission is the regulation of extracellular adenosine and because adenosine promotes sleep, we genetically inhibited the release of gliotransmitters and asked if astrocytes play an unsuspected role in sleep regulation. Inhibiting gliotransmission attenuated the accumulation of sleeppressure, assessed by measuring the slow wave activity of the EEG during NREM sleep, and prevented cognitive deficits associated with sleep loss. Since the sleep-suppressing effects of the A1 receptor antagonist CPT were prevented following inhibition of gliotransmission and because intracerebroventricular delivery of CPT to wild-type mice mimicked the transgenic phenotype, we conclude thatastrocytes modulate the accumulation of sleep pressure and its cognitive consequences through a pathway involving A1 receptors.
INTRODUCTION Although astrocytes are not electrically excitable, they exhibit Ca2+ elevations activated by metabotropic receptors. Natural stimuli such as whisker movement and visual gratings evoke astrocytic Ca2+ signals in the barrel (Wang et al., 2006) and visual cortices(Schummers et al., 2008). Synaptic activation of astrocytes leads to Ca2+ signals and in turn to the release of a number of chemical transmitters from these glia. This process of gliotransmission modulates synaptic activity (Jourdain et al., 2007; Pascual et al., 2005). Using molecular genetics we have shown that by releasing ATP, astrocytes regulate extracellular adenosine acting on synaptic A1receptors. Astrocytes release gliotransmitters via many pathways including exocytosis (Jourdain et al., 2007).

The exocytotic release of chemical transmitters depends on the formation of a SNARE complex between vesicles and the target membrane (Scales et al., 2000). Conditional astrocyteselective expression of the SNARE domain of the protein synaptobrevin II (dnSNARE) prevents both tonic andactivitydependent extracellular accumulation of adenosine that acts on A1 receptors in situ (Pascual et al., 2005). Adenosine is a transmitter involved in the homeostatic drive for sleep following prolonged wakefulness (Porkka-Heiskanen et al., 1997). However, the cellular source and mechanism of action of adenosine in the context of sleep are not well understood (Heller, 2006). Sinceastrocyte-dependent adenosine accumulation tonically regulates synaptic transmission and can be enhanced in an activity-dependent manner, this glial pathway of neuronal modulation is a prime candidate for mediating the progressive changes of the homeostatic drive for sleep. We therefore used astrocyte-specific transgenic mice to determine whether astrocytes contribute to this fundamental behavior. Becauseastrocytes release a number of transmitters, we additionally tested whether observed astrocyte-dependent transgenic phenotypes result from an adenosine deficit by using adenosinergic pharmacological agents in vivo to perform occlusion and mimicry experiments.

RESULTS Study Design and Rationale To inhibit the accumulation of astrocyte-derived adenosine, we used the tet-off system (Morozov et al., 2003)...