title: Astrocytes convert network excitation to tonic inhibition of neurons.
abstract: BACKGROUND
  Glutamate and γ-aminobutyric acid (GABA) transporters play important roles in balancing excitatory and inhibitory signals in the brain. Increasing evidence suggest that they may act concertedly to regulate extracellular levels of the neurotransmitters.
  
  
  RESULTS
  Here we present evidence that glutamate uptake-induced release of GABA from astrocytes has a direct impact on the excitability of pyramidal neurons in the hippocampus. We demonstrate that GABA, synthesized from the polyamine putrescine, is released from astrocytes by the reverse action of glial GABA transporter (GAT) subtypes GAT-2 or GAT-3. GABA release can be prevented by blocking glutamate uptake with the non-transportable inhibitor DHK, confirming that it is the glutamate transporter activity that triggers the reversal of GABA transporters, conceivably by elevating the intracellular Na+ concentration in astrocytes. The released GABA significantly contributes to the tonic inhibition of neurons in a network activity-dependent manner. Blockade of the Glu/GABA exchange mechanism increases the duration of seizure-like events in the low-[Mg2+] in vitro model of epilepsy. Under in vivo conditions the increased GABA release modulates the power of gamma range oscillation in the CA1 region, suggesting that the Glu/GABA exchange mechanism is also functioning in the intact hippocampus under physiological conditions.
  
  
  CONCLUSIONS
  The results suggest the existence of a novel molecular mechanism by which astrocytes transform glutamatergic excitation into GABAergic inhibition providing an adjustable, in situ negative feedback on the excitability of neurons.
authors.affiliation: Department of Functional Pharmacology, Institute of Molecular Pharmacology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Pusztaszeri 59-67, 1025 Budapest, Hungary. heja.laszlo@ttk.mta.hu
authors.forename: László
authors.initials: L
authors.lastname: Héja
authors.forename: Gabriella
authors.initials: G
authors.lastname: Nyitrai
authors.forename: Orsolya
authors.initials: O
authors.lastname: Kékesi
authors.forename: Arpád
authors.initials: A
authors.lastname: Dobolyi
authors.forename: Pál
authors.initials: P
authors.lastname: Szabó
authors.forename: Richárd
authors.initials: R
authors.lastname: Fiáth
authors.forename: István
authors.initials: I
authors.lastname: Ulbert
authors.forename: Borbála
authors.initials: B
authors.lastname: Pál-Szenthe
authors.forename: Miklós
authors.initials: M
authors.lastname: Palkovits
authors.forename: Julianna
authors.initials: J
authors.lastname: Kardos
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000378:metabolism / Q000503:physiopathology*; D025461:Feedback, Physiological; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D009433:Neural Inhibition; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; D050491:Glutamate Plasma Membrane Transport Proteins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase