Metabolic approach of absence seizures in a genetic model of absence epilepsy, the GAERS: Study of the leucine‐glutamate cycle

Abstract

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.

NIRS‐measured oxy‐ and deoxyhemoglobin changes associated with EEG spike‐and‐wave discharges in a genetic model of absence epilepsy: The GAERS

“…Our results are consistent with those of metabolic studies suggesting that the globally increased cerebral metabolic rate accompanying absence epilepsy (interictal and ictal periods taken together) may be due to seizure‐suppression mechanisms in rats (Nehlig et al., 1991, 1992; Dufour et al., 2001, 2003), children (Engel et al., 1982), and adults (Theodore et al., 1985). Another hypothesis is that childhood absence seizures may be caused by a reduced cortical inhibition, mediated by a mutation of the γ‐aminobutyric acid (GABA) receptors (Tan et al., 2007), leading to an increased excitability and cerebral metabolic rate.…”

Effects of Topiramate in Two Models of Genetically Determined Generalized Epilepsy, the GAERS and the Audiogenic Wistar AS

“…GABA A ‐receptor agonists, GABA transaminase inhibitors, and GABA reuptake inhibitors dose‐dependently increase the duration of SWDs (37,38), whereas glutamatergic N ‐methyl‐ d ‐aspartate (NMDA)‐receptor agonists, competitive and noncompetitive antagonists and antagonists of the glycine site suppress absence seizures in that strain (25,38). Recent data from our group led to the hypothesis that the occurrence of SWDs in GAERS would reflect a subtle imbalance between glutamate and GABA transmission (39) that occurs in the absence of any change in the basal levels of the amino acids (28). Any change in this subtle imbalance would thus prevent the expression of absence seizures.…”

Blinders, phenotype, and fashionable genetic analysis: A critical examination of the current state of epilepsy genetic studies

“…Brain energy metabolism is another area that could fruitfully be more widely explored. Defects in mitochondria lead to epilepsy (Fukuhara et al., 1980), that hypoglycemia can lead to seizures and neural damage (Arieff et al., 1974; Sapolsky & Stein, 1989; Velisek et al., 2008), that the ketogenic diet works for some patients with epilepsy, and that glucose metabolism syndromes can lead to seizures (Brockmann et al., 2001; Dufour et al., 2001; Yudkoff et al., 2001; Roll et al., 2002). We have found evidence that the ME2 gene, a Krebs cycle–related gene involved in neurotransmitter synthesis, is linked and associated with IGE (Greenberg et al., 2005).…”