Metabolic approach of absence seizures in a genetic model of absence epilepsy, the GAERS: study of the leucine-glutamate cycle.
We suggest that a dysregulation of energy metabolism in the brain of genetic absence epilepsy rats from Strasbourg (GAERS) could create a specific cerebral environment that would favor the expression of spike-and-wave discharges (SWD) in the thalamocortical loop, largely dependent on glutamatergic and gamma-aminobutyric acid (GABA)-ergic neurotransmissions. We tested several aspects of metabolic activity in the brain of GAERS compared to a genetic strain of nonepileptic (NE) rats. Glucose metabolism was higher in all brain regions of GAERS compared to those of NE rats along the whole glycolytic and aerobic pathways, as assessed by regional histochemical measurement of lactate dehydrogenase and cytochrome oxidase activities. Branched-chain amino acids (BCAA) and alpha-ketoisocaproate (alpha-KIC), the ketoacid of leucine, when injected intraperitoneally, increased the number of SWD in GAERS but had only a slight effect on their duration. These data speak in favor of a BCAA- or alpha-KIC-induced change in neuronal excitability. Leucine and alpha-KIC decreased the concentration of glutamate in thalamus and cortex without affecting GABA concentrations. Thus, BCAA and alpha-KIC, by decreasing glutamatergic neurotransmission, could favor GABAergic neurotransmission, which is known to increase the occurrence of seizures in GAERS. Finally, the transport of [1-(14)C]alpha-KIC in freshly isolated cortical neurons was lower in GAERS than in NE rats, and this difference was shown to be of metabolic origin. The addition of gabapentin, a specific inhibitor of BCAA transaminase (BCAT), reduced the transport of [1-(14)C]alpha-KIC in GAERS and NE rats to a level that became identical in both strains. This strain-dependent change was not related to a difference in the activity of BCAT, which was identical in GAERS and NE rats. The exact origin of this apparent metabolic dysregulation of energy metabolism in GAERS that could underlie the origin of seizures in that strain remains to be explored further.
Dufour
F
F
INSERM U 398, Faculty of Medicine, 11 rue Humann, 67085 Strasbourg, France.
Nalecz
K A
KA
Nalecz
M J
MJ
Nehlig
A
A
D000085:Acetates / Q000493:pharmacokinetics; D000588:Amines; D000597:Amino Acids, Branched-Chain / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002248:Carbon Monoxide / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics*; D004832:Epilepsy, Absence / Q000235:genetics / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D000077206:Gabapentin; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D007651:Keto Acids / Q000378:metabolism / Q000493:pharmacokinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007930:Leucine / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011922:Rats, Mutant Strains; D009435:Synaptic Transmission / Q000235:genetics*; D013572:Synaptic Vesicles / Q000378:metabolism; D000637:Transaminases / Q000378:metabolism; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D000597:Amino Acids, Branched-Chain; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D007651:Keto Acids; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D002248:Carbon Monoxide; C013082:alpha-ketoisocaproic acid; D007770:L-Lactate Dehydrogenase; D000637:Transaminases; C019798:branched-chain-amino-acid transaminase; D007930:Leucine; D005947:Glucose