Neuron
Volume 81, Issue 4, 19 February 2014, Pages 888-900
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Article
A Local Glutamate-Glutamine Cycle Sustains Synaptic Excitatory Transmitter Release

https://doi.org/10.1016/j.neuron.2013.12.026Get rights and content
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Highlights

  • Direct electrophysiological evidence for glutamine-glutamate cycle has been lacking

  • Isolated nerve terminals show an activity-dependent reduction in glutamate release

  • Exogenous glutamine (500 μM) fully prevents and reverses activity-induced run down

  • Astrocytic glutamine plays a crucial role in sustaining excitatory neurotransmission

Summary

Biochemical studies suggest that excitatory neurons are metabolically coupled with astrocytes to generate glutamate for release. However, the extent to which glutamatergic neurotransmission depends on this process remains controversial because direct electrophysiological evidence is lacking. The distance between cell bodies and axon terminals predicts that glutamine-glutamate cycle is synaptically localized. Hence, we investigated isolated nerve terminals in brain slices by transecting hippocampal Schaffer collaterals and cortical layer I axons. Stimulating with alternating periods of high frequency (20 Hz) and rest (0.2 Hz), we identified an activity-dependent reduction in synaptic efficacy that correlated with reduced glutamate release. This was enhanced by inhibition of astrocytic glutamine synthetase and reversed or prevented by exogenous glutamine. Importantly, this activity dependence was also revealed with an in-vivo-derived natural stimulus both at network and cellular levels. These data provide direct electrophysiological evidence that an astrocyte-dependent glutamate-glutamine cycle is required to maintain active neurotransmission at excitatory terminals.

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