Physiological synaptic activity and recognition memory require astroglial glutamine

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.

Hippocampal astrocytes modulate anxiety-like behavior

“…Activated astrocytes release various gliotransmitters, including glutamate 34 and D-serine 35 . Although we did not detect a significant increase in glutamate or D-serine in our study, we cannot exclude the possibility that these gliotransmitters are released from hippocampal astrocytes in response to other stimuli or behavioral contexts and thereby affect other hippocampus-dependent behaviors 35 , 36 . Indeed, previous studies have revealed a role of hippocampal astrocytes in memory functions.…”

Astrocytes in CA1 modulate schema establishment in the hippocampal-cortical neuron network

“…We showed that prior schema manipulation by CA1 astrocyte Gi activation leads to impaired memory performance associated with suppression of CA1 and ACC neural excitation during multiple PA training, suggesting that it failed to develop schematic memory. Studies have shown that astrocytic glutamate modulates HPC synaptic plasticity by activating postsynaptic NMDA receptors [ 39 , 40 ] which is necessary in schema PA encoding [ 22 ]. It has been reported that astrocytic Gi pathway activation can decrease astrocytic intracellular Ca 2+ levels and Ca 2+ events [ 19 ], suggesting that the disruption of schema memory by astrocytic Gi pathway modulation may be a result of gliotransmitter release disruption.…”

Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2

“…Glutamine supplies nitrogen and carbon for biosynthetic reactions in rapidly proliferating cells,65 but in many contexts its key role relies on providing glutamate (figure 4) which has a wider range of metabolic functions than glutamine itself. An example of the relevant functions of glutamine and glutamate is the glutamate/GABA-glutamine cycle in neurons 66. In fact, it has been stated that alterations of the GABAergic system may play an important role in aspects of the pathophysiology of PWS 67.…”

“…An example of the relevant functions of glutamine and glutamate is the glutamate/GABA-glutamine cycle in neurons. 66 In fact, it has been stated that alterations of the GABAergic system may play an important role in aspects of the pathophysiology of PWS. 67 A hypothesis to explain the decrease in glutamine levels in SYS fibroblasts could be a dysregulation in the retrieval and recycling of a glutamine transporter, such as SLC1A5, whose retrieval and recycling is promoted by the retromer and whose degradation is enhanced on retromer knockout.…”