Maintenance of thalamic epileptiform activity depends on the astrocytic glutamate-glutamine cycle.
The generation of prolonged neuronal activity depends on the maintenance of synaptic neurotransmitter pools. The astrocytic glutamate-glutamine cycle is a major mechanism for recycling the neurotransmitters GABA and glutamate. Here we tested the effect of disrupting the glutamate-glutamine cycle on two types of neuronal activity patterns in the thalamus: sleep-related spindles and epileptiform oscillations. In recording conditions believed to induce glutamine scarcity, epileptiform oscillations showed a progressive reduction in duration that was partially reversible by the application of exogenous glutamine (300 muM). Blocking uptake of glutamine into neurons with alpha-(methylamino) isobutyric acid (5 mM) caused a similar reduction in oscillation duration, as did blocking neuronal GABA synthesis with 3-mercaptoproprionic acid (10 muM). However, comparable manipulations did not affect sleep spindles. Together, these results support a crucial role for the glutamate-glutamine cycle in providing the neurotransmitters necessary for the generation of epileptiform activity and suggest potential therapeutic approaches that selectively reduce seizure activity but maintain normal neuronal activity.
Bryant
Astra S
AS
Department of Neurology and Neurological Sciences, Stanford University, Stanford, California 94305-5122, USA.
Li
Bojia
B
Beenhakker
Mark P
MP
Huguenard
John R
JR
D015097:3-Mercaptopropionic Acid / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D001640:Bicuculline / Q000031:analogs & derivatives / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D005973:Glutamine / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013788:Thalamus / Q000166:cytology*; D013997:Time Factors
D003292:Convulsants; D005973:Glutamine; D018698:Glutamic Acid; C017069:bicuculline methiodide; D015097:3-Mercaptopropionic Acid; D001640:Bicuculline