Decreased expression of glutamate transporters in genetic absence epilepsy rats before seizure occurrence

Abstract

In absence epilepsy, epileptogenic processes are suspected of involving an imbalance between GABAergic inhibition and glutamatergic excitation. Here, we describe alteration of the expression of glutamate transporters in rats with genetic absence (the Genetic Absence Epilepsy Rats from Strasbourg: GAERS). In these rats, epileptic discharges, recorded in the thalamo-cortical network, appear around 40 days after birth. In adult rats no alteration of the protein expression of the glutamate transporters was observed. In 30-day-old GAERS protein levels (quantified by western blot) were lower in the cortex by 21% and 35% for the glial transporters GLT1 and GLAST, respectively, and by 32% for the neuronal transporter EAAC1 in the thalamus compared to control rats. In addition, the expression and activity of GLAST were decreased by 50% in newborn GAERS cortical astrocytes grown in primary culture. The lack of modification of the protein levels of glutamatergic transporters in adult epileptic GAERS, in spite of mRNA variations (quantified by RT-PCR), suggests that they are not involved in the pathogeny of spike-and-wave discharges. In contrast, the alteration of glutamate transporter expression, observed before the establishment of epileptic discharges, could reflect an abnormal maturation of the glutamatergic neurone-glia circuitry. Keywords: cortex, EAAC1, GAERS, GLAST, GLT1, thalamus. Absence epilepsy is mainly a childhood disease. Seizures occur as frequently as several hundred times per day and are detrimental to children's education and health. While convulsive epilepsy has been widely investigated, little is known about the pathophysiology of absence seizures. In GAERS (Genetic Absence Epilepsy Rats from Strasbourg), a genetic model of absence epilepsy (Vergnes et al. 1982), epileptic seizures occur around 40 days after birth and persist throughout lifetime. As in the human disease, the neuronal hyperexcitation and hypersynchronization, which induce spike-and-wave discharges (SWDs) in GAERS, are generated in a cortico-thalamic loop, involving reciprocal glutamatergic projections between the thalamus and the cortex, as well as GABAergic interneurones. Involvement of GABA and glutamate in the initiation and spreading of epileptic discharges in this model is supported by electrophysiological and pharmacological studies. A significantly increased amplitude of the voltage-dependent low-threshold Ca 2+ current observed in the reticular thalamic nucleus of GAERS with established epilepsy suggests an alteration of the GABAergic neurones in this structure (Tsakiridou et al. 1995). GABA A and GABA B agonists increase the duration of SWDs, while GABA B antagonists suppress SWDs. In addition, agonists of the glutamate receptor AMPA increase SWDs, while AMPA and NMDA antagonists decrease and suppress them, respectively. Density of GABAergic or glutamatergic neurones, glutamate decarboxylase expression (GABA synthesizing enzyme) and density of GABA

Modulation of astrocyte glutamate transporters decreases seizures in a mouse model of Tuberous Sclerosis Complex

“…For example, expression of the astrocyte glutamate transporter, GLT-1, is dramatically decreased in human ALS and mouse models (Rothstein et al, 1995; Howland et al, 2002). Similarly, abnormalities in glutamate transporter expression have been reported in various animal models of epilepsy (Miller et al, 1997; Akbar et al, 1998; Samuelsson et al, 2000; Ingram et al, 2001; Dutuit et al, 2002; Harrington et al, 2007), as well as in human brain specimens resected from epilepsy patients (Mathern et al, 1999; Tessler et al, 1999; Crino et al, 2002; Proper et al, 2002). Furthermore, genetic or pharmacological manipulations that decrease astrocyte glutamate transporters can induce an epileptic phenotype in rodents (Tanaka et al, 1997; Watanabe et al, 1999; Milh et al, 2007).…”

Increased thalamus levels of glutamate and glutamine (Glx) in patients with idiopathic generalised epilepsy

“…36 37 One suggested mechanism for the elevated extracellular glutamate concentration in epilepsy is the reduction in glutamate reuptake. The levels of glutamate transporters are decreased prior to seizure occurrence in the cortex and the thalamus, 38 which underlines the possible involvement of glutamine and glutamate transmission in this region.…”

Mitochondria, oxidative stress, and temporal lobe epilepsy

“…An increase in GLAST mRNA and GLT-1 expression has also been reported (Nonaka et al, 1998) along with a decrease in EAAT-3 mRNA (Akbar et al, 1998). Further, decreased expression of GLT-1 and GLAST has been observed in the cortex of rats with genetic absence epilepsy (Dutuit et al, 2002) and in the hippocampus of epileptic EL mice (Ingram et al, 2001). Additionally, the expression of GLT-1, GLAST, and EAAC-1, were reported to decrease in epileptic Sod2 −/+ and Sod2 +/+ mice at increasing ages (Liang and Patel, 2004).…”