Researchers are increasingly aware that astrocytes respond to neuronal activity with Ca2+ signals that can induce the release of chemical transmitters. The roles of these gliotransmitters in the control of neural function and behavior are poorly defined. Our studies have revealed that astrocytes are responsible for the control of extracellular adenosine that activates neuronal adenosine 1 receptors (A1R). The expression of a dominant negative dnSNARE domain in astrocytes, to inhibit the release of gliotransmitters, causes a reduction in the magnitude of CA3-CA1 long term potentiation (LTP)(Pascual et al., 2005) as well as a reduction in synaptic Nmethyl-D-spartate receptor (NMDAR) current (prelim studies) and impairments in sleep homeostasis. Since Ca2+ supplied by NMDARs is essential for the induction of LTP, we propose a novel hypothesis linking astrocyte-derived adenosine with NMDARs and LTP: Astrocyte-derived adenosine acting through A1 receptors enhances synaptic NMDAR currents and consequently the magnitude of NMDAR-dependent LTP. To test this hypothesis we will use conditional astrocyte-specific transgenic mice that allow both activation and inhibition of glial signaling pathways. We have four specific aims: First, we will test the hypothesis that astrocyte-derived adenosine acting on A1 receptors regulates synaptic NMDAR currents. Second, we will test the hypothesis that astrocytic Ca2+ signaling promotes NMDAR-dependent LTP. Third, we will test the hypothesis that astrocytic enhancement of LTP is mediated via A1 receptor-dependent augmentation of NMDA receptors. There are likely to be wide ranging effects of adenosine, NMDAR and LTP on behavior. To maintain focus we will build on our recent studies in the fourth specific aim to identify roles for astrocyte-Ca2+ signals and adenosine in the control of sleep homeostasis. This project will provide entirely new information on the role of astrocytes in brain function. Using molecular genetic studies in situ and in vivo we will determine under which conditions astrocytes contribute to information processing and behavior. Since we propose that astrocyte-derived signals regulate NMDA receptors, receptors known to be central to numerous disorders, this project has the potential to identify novel glial targets to enhance learning and memory and to treat sleep disorders. PUBLIC HEALTH REVELANCE: This project tests the hypothesis that non-neuronal cells of the brain called astrocytes regulate neuronal receptors that are essential for synaptic plasticity and learning and memory. Because these receptors are thought to be involved in several disorders, this project has the potential to identify novel therapeutic targets for disorders including sleep disorders, epilepsy, stroke and schizophrenia.

Public Health Relevance

This project tests the hypothesis that non-neuronal cells of the brain called astrocytes regulate neuronal receptors that are essential for synaptic plasticity and learning and memory. Because these receptors are thought to be involved in several disorders, this project has the potential to identify novel therapeutic targets for disorders including sleep disorders, epilepsy, stroke and schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037585-15
Application #
8120577
Study Section
Special Emphasis Panel (ZRG1-MDCN-F (02))
Program Officer
Morris, Jill A
Project Start
1998-04-01
Project End
2014-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
15
Fiscal Year
2011
Total Cost
$408,212
Indirect Cost
Name
Tufts University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Papouin, Thomas; Dunphy, Jaclyn; Tolman, Michaela et al. (2017) Astrocytic control of synaptic function. Philos Trans R Soc Lond B Biol Sci 372:
Foley, Jeannine; Blutstein, Tamara; Lee, SoYoung et al. (2017) Astrocytic IP3/Ca2+ Signaling Modulates Theta Rhythm and REM Sleep. Front Neural Circuits 11:3
Clasadonte, Jerome; Scemes, Eliana; Wang, Zhongya et al. (2017) Connexin 43-Mediated Astroglial Metabolic Networks Contribute to the Regulation of the Sleep-Wake Cycle. Neuron 95:1365-1380.e5
Haydon, Philip G (2017) Astrocytes and the modulation of sleep. Curr Opin Neurobiol 44:28-33
Keck, Tara; Toyoizumi, Taro; Chen, Lu et al. (2017) Integrating Hebbian and homeostatic plasticity: the current state of the field and future research directions. Philos Trans R Soc Lond B Biol Sci 372:
Papouin, Thomas; Dunphy, Jaclyn M; Tolman, Michaela et al. (2017) Septal Cholinergic Neuromodulation Tunes the Astrocyte-Dependent Gating of Hippocampal NMDA Receptors to Wakefulness. Neuron 94:840-854.e7
Haydon, Philip G (2016) The Evolving View of Astrocytes. Cerebrum 2016:
Walker, Kendall R; Modgil, Amit; Albrecht, David et al. (2016) Genetic Deletion of the Clathrin Adaptor GGA3 Reduces Anxiety and Alters GABAergic Transmission. PLoS One 11:e0155799
Araque, Alfonso; Carmignoto, Giorgio; Haydon, Philip G et al. (2014) Gliotransmitters travel in time and space. Neuron 81:728-39
Clasadonte, Jerome; McIver, Sally R; Schmitt, Luke I et al. (2014) Chronic sleep restriction disrupts sleep homeostasis and behavioral sensitivity to alcohol by reducing the extracellular accumulation of adenosine. J Neurosci 34:1879-91

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