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 N- methyl-D-aspartate 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.
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.
|Kawamata, Hibiki; Ng, Seng Kah; Diaz, Natalia et al. (2014) Abnormal intracellular calcium signaling and SNARE-dependent exocytosis contributes to SOD1G93A astrocyte-mediated toxicity in amyotrophic lateral sclerosis. J Neurosci 34:2331-48|
|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|
|Araque, Alfonso; Carmignoto, Giorgio; Haydon, Philip G et al. (2014) Gliotransmitters travel in time and space. Neuron 81:728-39|
|Nadjar, Agnes; Blutstein, Tamara; Aubert, Agnes et al. (2013) Astrocyte-derived adenosine modulates increased sleep pressure during inflammatory response. Glia 61:724-31|
|Hines, Rochelle M; Hines, Dustin J; Houston, Catriona M et al. (2013) Disrupting the clustering of GABAA receptor *2 subunits in the frontal cortex leads to reduced ýý-power and cognitive deficits. Proc Natl Acad Sci U S A 110:16628-33|
|Vithlani, Mansi; Hines, Rochelle M; Zhong, Ping et al. (2013) The ability of BDNF to modify neurogenesis and depressive-like behaviors is dependent upon phosphorylation of tyrosine residues 365/367 in the GABA(A)-receptor ýý2 subunit. J Neurosci 33:15567-77|
|Blutstein, Tamara; Haydon, Philip G (2013) The Importance of astrocyte-derived purines in the modulation of sleep. Glia 61:129-39|
|Schmitt, L Ian; Sims, Robert E; Dale, Nicholas et al. (2012) Wakefulness affects synaptic and network activity by increasing extracellular astrocyte-derived adenosine. J Neurosci 32:4417-25|
|Deng, Qiudong; Terunuma, Miho; Fellin, Tommaso et al. (2011) Astrocytic activation of A1 receptors regulates the surface expression of NMDA receptors through a Src kinase dependent pathway. Glia 59:1084-93|
|Florian, Cedrick; Vecsey, Christopher G; Halassa, Michael M et al. (2011) Astrocyte-derived adenosine and A1 receptor activity contribute to sleep loss-induced deficits in hippocampal synaptic plasticity and memory in mice. J Neurosci 31:6956-62|
Showing the most recent 10 out of 28 publications