Reciprocal signaling between synapses and astrocytes

University Of Pennsylvania, Philadelphia PA

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Abstract

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 IV: By integrating the overall level of neuronal activity astrocytes have anti-convulsant actions through their control of extracellular adenosine.