title: Glutamine uptake by System A transporters maintains neurotransmitter GABA synthesis and inhibitory synaptic transmission.
abstract: GABA synthesis is necessary to maintain synaptic vesicle filling, and key proteins in its biosynthetic pathways may play a role in regulating inhibitory synaptic stability and strength. GABAergic neurons require a source of precursor glutamate, possibly from glutamine, although it is controversial whether glutamine contributes to the synaptic pool of GABA. Here we report that inhibition of System A glutamine transporters with alpha-(methyl-amino) isobutyric acid rapidly reduced the amplitude of inhibitory post-synaptic currents and miniature inhibitory post-synaptic currents (mIPSCs) recorded in rat hippocampal area cornu ammonis 1 (CA1) pyramidal neurons, indicating that synaptic vesicle content of GABA was reduced. After inhibiting astrocytic glutamine synthesis by either blocking glutamate transporters or the glutamine synthetic enzyme, the effect of alpha-(methyl-amino) isobutyric acid on mIPSC amplitudes was abolished. Exogenous glutamine did not affect mIPSC amplitudes, suggesting that the neuronal transporters are normally saturated. Our findings demonstrate that a constitutive supply of glutamine is provided by astrocytes to inhibitory neurons to maintain vesicle filling. Therefore, glutamine transporters, like those for glutamate, are potential regulators of inhibitory synaptic strength. However, in contrast to glutamate, extracellular glutamine levels are normally high. Therefore, we propose a supportive role for glutamine, even under resting conditions, to maintain GABA vesicle filling.
authors.affiliation: Department of Neurology, Vanderbilt University, Nashville, Tennessee, USADepartment of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Molly N
authors.initials: MN
authors.lastname: Fricke
authors.affiliation: Department of Neurology, Vanderbilt University, Nashville, Tennessee, USADepartment of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Dorothy M
authors.initials: DM
authors.lastname: Jones-Davis
authors.affiliation: Department of Neurology, Vanderbilt University, Nashville, Tennessee, USADepartment of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Mathews
mesh_terms: D026924:Amino Acid Transport System A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000621:Aminoisobutyric Acids / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000502:physiology*; D009924:Organ Culture Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis*
chemical_list: D026924:Amino Acid Transport System A; D000621:Aminoisobutyric Acids; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; C037853:glutamine transport proteins; C017911:2-(methylamino)isobutyric acid; D005680:gamma-Aminobutyric Acid