Control of hippocampal synaptic transmission and plasticity by wakefulnessdependent elevation of astrocyte-derived adenosine.
Abstract: Sleep is a
highly conserved behavior which is critically important to the function of the nervous
system and in particular to consolidation of declarative memory. Recent evidence has
suggested that astrocytes, the major glial support cell within the brain, play a key
role in maintaining sleep homeostasis by governing the level of adenosine which acts in
extracellular space to regula... read morete synaptic transmission. In addition, adenosine signaling
by these cells has been implicated in the regulation of hippocampal dependent memory,
suggesting that they play a previously unrecognized role in information processing
within this brain area. Although it is increasingly evident that astrocytes can listen
and respond to neurotransmission through calcium dependent exocytotic release, the
mechanism by which they respond to wakefulness to affect synaptic transmission remains
poorly understood. In this dissertation, I present the results of my investigations into
the role of astrocyte-derived adenosine in wakefulness-dependent changes to synaptic
transmission and neuroplasticity within the hippocampus. Using a variety of
electrophysiological means combined with molecular genetic disruption of astrocytic
exocytosis and Inositol tri-Phosphate (IP3) signaling in these cells, I demonstrate for
the first time that wakefulness can regulate the level of astrocyte-derived adenosine
acting in the hippocampus. I show that acute loss of sleep leads to an increase in
signaling by this transmitter, while extended sleep loss produces an allostatic
adjustment to reduce the level of adenosine, probably through reduced release, thereby
compensating for the effects of chronic sleep disruption. Finally, I show that the
mechanism by which astrocytes control extracellular adenosine depends on IP3 calcium
mobilization in these cells and that over short time scales astrocyte-derived adenosine
can both inhibit synaptic release of glutamate and enhance synaptic plasticity by
increasing NMDA receptor mediated responses. Because of the critical importance of sleep
in maintaining the health of the nervous system and the comorbidity of sleep pathologies
in various neurological and psychiatric disorders, these results hold important
implications for understanding the role of both astrocytes and adenosine signaling in
health and disease.
Thesis (Ph.D.)--Tufts University, 2014.
Submitted to the Dept. of Neuroscience.
Advisor: Philip Haydon.
Committee: F. Jackson, Michelle Jacob, and Kathleen Dunlap.
Keyword: Neurosciences.read less