Neuromodulatory roles for astrocytes: Synapses, circuits & behavior

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