Glutamate uptake triggers transporter-mediated GABA release from astrocytes.
BACKGROUND
Glutamate (Glu) and gamma-aminobutyric acid (GABA) transporters play important roles in regulating neuronal activity. Glu is removed from the extracellular space dominantly by glial transporters. In contrast, GABA is mainly taken up by neurons. However, the glial GABA transporter subtypes share their localization with the Glu transporters and their expression is confined to the same subpopulation of astrocytes, raising the possibility of cooperation between Glu and GABA transport processes.


RESULTS
Here we used diverse biological models both in vitro and in vivo to explore the interplay between these processes. We found that removal of Glu by astrocytic transporters triggers an elevation in the extracellular level of GABA. This coupling between excitatory and inhibitory signaling was found to be independent of Glu receptor-mediated depolarization, external presence of Ca(2+) and glutamate decarboxylase activity. It was abolished in the presence of non-transportable blockers of glial Glu or GABA transporters, suggesting that the concerted action of these transporters underlies the process.


CONCLUSIONS
Our results suggest that activation of Glu transporters results in GABA release through reversal of glial GABA transporters. This transporter-mediated interplay represents a direct link between inhibitory and excitatory neurotransmission and may function as a negative feedback combating intense excitation in pathological conditions such as epilepsy or ischemia.
Department of Neurochemistry, Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences, Budapest, Hungary. heja@chemres.hu
László
L
Héja
Péter
P
Barabás
Gabriella
G
Nyitrai
Katalin A
KA
Kékesi
Bálint
B
Lasztóczi
Orsolya
O
Toke
Gábor
G
Tárkányi
Karsten
K
Madsen
Arne
A
Schousboe
Arpád
A
Dobolyi
Miklós
M
Palkovits
Julianna
J
Kardos
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D051381:Rats; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D050485:GABA Plasma Membrane Transport Proteins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase