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Neuron. 2014 Feb 19;81(4):888-900. doi: 10.1016/j.neuron.2013.12.026.

A local glutamate-glutamine cycle sustains synaptic excitatory transmitter release.

Author information

1
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: hirotaniwork@gmail.com.
2
Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA.
3
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Graduate Program in Neuroscience, Stanford University School of Medicine, Stanford, CA 94305, USA.
4
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Graduate Program in Neuroscience, Stanford University School of Medicine, Stanford, CA 94305, USA; Neurology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA. Electronic address: rjreimer@stanford.edu.

Abstract

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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PMID:
24559677
PMCID:
PMC4001919
DOI:
10.1016/j.neuron.2013.12.026
[Indexed for MEDLINE]
Free PMC Article

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