Abstract
Presynaptic glutamate replenishment is fundamental to brain function. In high activity regimes, such as epileptic episodes, this process is thought to rely on the glutamate-glutamine cycle between neurons and astrocytes. However the presence of an astroglial glutamine supply, as well as its functional relevance in vivo in the healthy brain remain controversial, partly due to a lack of tools that can directly examine glutamine transfer. Here, we generated a fluorescent probe that tracks glutamine in live cells, which provides direct visual evidence of an activity-dependent glutamine supply from astroglial networks to presynaptic structures under physiological conditions. This mobilization is mediated by connexin43, an astroglial protein with both gap-junction and hemichannel functions, and is essential for synaptic transmission and object recognition memory. Our findings uncover an indispensable recruitment of astroglial glutamine in physiological synaptic activity and memory via an unconventional pathway, thus providing an astrocyte basis for cognitive processes.
Highlights
Presynaptic glutamate replenishment is fundamental to brain function
Because the presynaptic pool of glutamate contributes to recognition memory[34], we investigated in vivo the functional significance of connexin 43 (Cx43) HC-mediated release of glutamine in such form of hippocampal memory
We identified astroglial Cx43 HCs as the key mediators of this process, essential for sustaining physiological excitatory synaptic transmission as well as recognition memory
Summary
Presynaptic glutamate replenishment is fundamental to brain function. In high activity regimes, such as epileptic episodes, this process is thought to rely on the glutamateglutamine cycle between neurons and astrocytes. We generated a fluorescent probe that tracks glutamine in live cells, which provides direct visual evidence of an activity-dependent glutamine supply from astroglial networks to presynaptic structures under physiological conditions. This mobilization is mediated by connexin[43], an astroglial protein with both gap-junction and hemichannel functions, and is essential for synaptic transmission and object recognition memory. It was estimated that, without replenishment, the pool of presynaptic glutamate would be exhausted within a minute of basal synaptic activity[6] While this cycle has been implicated in epilepsy, a hyperactive state where the rate of glutamate release is greatly enhanced[7,8,9], its relevance to physiological conditions is still under debate due to conflicting reports. We find that the role of glutamine is dependent on the opening of astroglial connexin 43 hemichannels upon activity, and provide evidence for the functional relevance of astroglial glutamine in physiological synaptic transmission and cognition
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