Glial modulation of GABAergic and glutamat ergic neurotransmission.
Function of astroglia in the modulation of availability, release and clearance (inactivation) of Glu and GABA within the central nervous system is reviewed. Net synthesis of Glu through Gln synthetase exclusively localized in astrocytes can only occur by a metabolic coupling between neurons and astrocytes. Two (GLAST and GLT-1) of the five Glu transporters cloned preferentially expressed in astrocytes perform the astroglial Glu uptake of very high capacity. Moreover, astrocytes have been shown to mediate Glu release by a mechanism mimicking vesicular release. Biosynthesis of GABA in neurons is brought about by decarboxylation of Glu catalyzed by a pyridoxal phosphate requiring enzyme (GAD) that exists in two isoforms (GAD65 and GAD67) exhibiting different subcellular localization and regulatory properties. Detailed studies of GABA synthesis in GABAergic neurons using (13)C NMR spectroscopy have provided evidence for direct involvement of the tricarboxylic acid cycle. Synaptically released GABA taken up into surrounding astrocytes is converted to either CO(2) or Gln. Two reports on the release of GABA in rat dorsal root ganglia indicated that glial cells may perform GABA release as well. Gln formed from GABA in astrocytes can be transferred to GABAergic neurons and subsequently converted to GABA. Inhibition of either degradation or clearance of GABA has been successfully applied in the development of antiepileptics such as vigabatrin or tiagabine. So far, no specific strategy has been developed aimed at stimulating Glu transport.
Schousboe
Arne
A
Department of Pharmacology and Pharmacotherapy, Danish University of Pharmaceutical Sciences, Copenhahgen. as@dfuni.dk
Waagepetersen
Helle S
HS
D000818:Animals; D018698:Glutamic Acid / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid