title: A local glutamate-glutamine cycle sustains synaptic excitatory transmitter release.
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.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: hirotaniwork@gmail.com.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tani
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Chris G
authors.initials: CG
authors.lastname: Dulla
authors.affiliation: 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.
authors.forename: Zoya
authors.initials: Z
authors.lastname: Farzampour
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Amaro
authors.initials: A
authors.lastname: Taylor-Weiner
authors.affiliation: 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.
authors.forename: John R
authors.initials: JR
authors.lastname: Huguenard
authors.affiliation: 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.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Reimer
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005971:Glutamates / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D005971:Glutamates; D005973:Glutamine