Activation of glutamate transport evokes rapid glutamine release from perisynaptic astrocytes


B. Billups: Department of Pharmacology, Tennis Court Road, Cambridge CB2 1PD, UK. Email:


Key points 

  • • Following release of glutamate from excitatory synapses, excitatory amino acid transporters (EAATs) sequester this glutamate into neighbouring astrocytes.
  • • The signalling effects on the astrocyte and the mechanisms by which this glutamate is recycled back to the synapse are currently unclear.
  • • In this study we use electrophysiological recording from neurones and astrocytes to show that a surge of the neurotransmitter glutamate, as usually occurs during neuronal activity, activates astrocytes and causes them to rapidly release the amino acid glutamine.
  • • This glutamine mediates a fast signal back to the neurones, where it is sequestered and is available for the biosynthesis of further neurotransmitters.
  • • Our data demonstrate a novel feedback mechanism by which astrocytes can potentially modulate neuronal function, and pave the way for development of new therapeutic approaches to treat neurological disorders.


Abstract  Stimulation of astrocytes by neuronal activity and the subsequent release of neuromodulators is thought to be an important regulator of synaptic communication. In this study we show that astrocytes juxtaposed to the glutamatergic calyx of Held synapse in the rat medial nucleus of the trapezoid body (MNTB) are stimulated by the activation of glutamate transporters and consequently release glutamine on a very rapid timescale. MNTB principal neurones express electrogenic system A glutamine transporters, and were exploited as glutamine sensors in this study. By simultaneous whole-cell voltage clamping astrocytes and neighbouring MNTB neurones in brainstem slices, we show that application of the excitatory amino acid transporter (EAAT) substrate d-aspartate stimulates astrocytes to rapidly release glutamine, which is detected by nearby MNTB neurones. This release is significantly reduced by the toxins l-methionine sulfoximine and fluoroacetate, which reduce glutamine concentrations specifically in glial cells. Similarly, glutamine release was also inhibited by localised inactivation of EAATs in individual astrocytes, using internal dl-threo-β-benzyloxyaspartic acid (TBOA) or dissipating the driving force by modifying the patch-pipette solution. These results demonstrate that astrocytes adjacent to glutamatergic synapses can release glutamine in a temporally precise, controlled manner in response to glial glutamate transporter activation. Since glutamine can be used by neurones as a precursor for glutamate and GABA synthesis, this represents a potential feedback mechanism by which astrocytes can respond to synaptic activation and react in a way that sustains or enhances further communication. This would therefore represent an additional manifestation of the tripartite relationship between synapses and astrocytes.