During the past decade a surge of experimental evidence has shown that astrocytes release chemical transmitters which modulate synaptic transmission and neuronal excitability. In addition to taking up synaptically released neurotransmitters, astrocytes release glutamate, ATP and D-serine. Though it is now clear that astrocytes listen and talk to synapses, the functional implications of this bi-directional signaling pathway are not yet clear. During the past funding period we have generated astrocyte-specific inducible transgenic mice in which we can block the release of the chemical transmitter ATP from astrocytes in adult animals. With this mouse we have discovered that astrocytes coordinate synaptic networks by regulating the extracellular concentration of adenosine: astrocyte-released ATP is hydrolyzed to adenosine which suppresses the strength of excitatory synaptic transmission. The availability of this transgenic animal puts us in the unique position to test the following hypothesis. """"""""Activity dependent release of ATP from astrocytes leads to the accumulation of extracellular adenosine that suppresses synaptic transmission neuronal excitability. The astrocyte-dependent accumulation of adenosine acts as a spatial filter, enhancing the contrast between neighboring synaptic pathways and limits the spread of excitation thereby suppressing the development of seizures."""""""" Using molecular genetics together with brain slice electrophysiology we will perform four specific aims of investigation:
Aim I : We will test the hypothesis that the diacylglycerol arm of the phospholipase C (PLC) pathway is required to stimulate ATP release from astrocytes.
Aim II : Synaptically stimulated release of purines from astrocytes causes a contrast-enhancement between neighboring active and inactive synapses.
Aim III : Astrocyte-derived purines block the induction of LTP.
Aim I V: By integrating the overall level of neuronal activity astrocytes have anti-convulsant actions through their control of extracellular adenosine.
| Carmignoto, Giorgio; Haydon, Philip G (2012) Astrocyte calcium signaling and epilepsy. Glia 60:1227-33 |
| Lee, So-Young; Haydon, Philip G (2011) A cytokine-dependent switch for glial-neuron interactions. Neuron 69:835-7 |
| Florian, Cédrick; 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 |
| Dong, Jinghui; Revilla-Sanchez, Raquel; Moss, Stephen et al. (2010) Multiphoton in vivo imaging of amyloid in animal models of Alzheimer's disease. Neuropharmacology 59:268-75 |
| Halassa, Michael M; Haydon, Philip G (2010) Integrated brain circuits: astrocytic networks modulate neuronal activity and behavior. Annu Rev Physiol 72:335-55 |
| Potokar, Maja; Kreft, Marko; Lee, So-Young et al. (2009) Trafficking of astrocytic vesicles in hippocampal slices. Biochem Biophys Res Commun 390:1192-6 |
| Halassa, Michael M; Fellin, Tommaso; Haydon, Philip G (2009) Tripartite synapses: roles for astrocytic purines in the control of synaptic physiology and behavior. Neuropharmacology 57:343-6 |
| Haydon, Philip G; Blendy, Julie; Moss, Stephen J et al. (2009) Astrocytic control of synaptic transmission and plasticity: a target for drugs of abuse? Neuropharmacology 56 Suppl 1:83-90 |
| Halassa, Michael M; Florian, Cedrick; Fellin, Tommaso et al. (2009) Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron 61:213-9 |
| Halassa, Michael M; Fellin, Tommaso; Takano, Hajime et al. (2007) Synaptic islands defined by the territory of a single astrocyte. J Neurosci 27:6473-7 |
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