| In addition to being structurally associated with synapses, astrocytes are now known to be functionally involved in the modulation of synaptic transmission. Astrocytes express a number of G-protein coupled receptors (GPCRs) which allow them to respond to nearby synaptic activity by an IP 3-dependent rise in intracellular Ca2+.;Fifteen years ago, the Haydon lab discovered that astrocytes are able to release chemical transmitters that influence nearby neurons in a process termed gliotransmission, demonstrating that astrocytes not only "listen" to synapses, but can also "talk" back. In my thesis, I first describe the detailed three dimensional relationships between astrocytes and neurons in the mammalian neocortex. I show that cortical astrocytes occupy non-overlapping territories and that a single astrocyte contacts, on average, four neuronal cell bodies and hundreds of dendrites.;Second, I generate a transgenic animal in which a venus-tagged IP 3 5-phosphatase (VIPP) fusion protein is selectively and conditionally expressed in astrocytes to attenuate IP3-dependent Ca2+ signaling. In hippocampal suces derived from the VIPP mice, agonist induced Ca2+ signaling in astrocytes and theta-burst induced LTP are significantly attenuated.;Third, by using a transgenic animal in which SNARE-dependent gliotransmission is attenuated by the overexpression of a dominant negative SNARE domain (dnSNARE) specifically and conditionally in astrocytes, I show that sleep homeostasis and memory impairment following sleep loss are under the control of astrocytic adenosine. I corroborate these findings by an independent pharmacological approach in vivo. This study is the first to show a direct behavioral consequence for gliotransmission in mammals.;Combined these studies offer an insight into the structural and functional relationship between astrocytes and neurons and to the role of gliotransmission in controlling synapses, circuits and behavior. |
