Many epileptic syndromes develop from treatable to pharmaco-resistant forms of the disease. Thus it is desirable to develop new strategies for the treatment of patients who are refractory to presently available anticonvulsant drugs.

Glutamate can be converted to the inhibitory neurotransmitter GABA after neuronal uptake. Furthermore, it has been shown that blockade of glutamate uptake into glia cells increases the GABA amount filled into neuronal vesicles thereby enhancing the inhibitory strength.

In the present study, we tested the effect of glutamate uptake blockers on acutely induced epileptiform activity in hippocampo-entorhinal rat slices. Epileptiform activity was induced by three different approaches: by increasing excitation levels due to the lack of magnesium-ions (NMDA-receptor facilitation); by applying 4-aminopyridine (potassium channel block); by reducing inhibition with the GABA receptor antagonist penicillin. Epileptiform activity was recorded in the hippocampal region CA1 and in entorhinal cortex (EC). To block glutamate uptake we used dihydrokainate (DHK), a specific antagonist of the glial glutamate transporter GLT1, and threo-beta-benzyloxyaspartic acid (TBOA), an unspecific blocker of glial and neuronal glutamate uptake. In CA1, DHK dose-dependently reduced the frequency of epileptiform discharges in the low-magnesium model to 9% (50mM) / 0% (300mM). In the 4-AP model short spontaneous population bursts were reduced to 14% by 300mM DHK. TBOA (30mM) caused a reduction to 17% in the low magnesium and to 15% in the 4-AP model. Penicillin-induced epileptiform discharges, however, were facilitated after glutamate uptake block (1026% by 300mM DHK and 269% by 30mM TBOA). While DHK and TBOA reduced frequency in CA1 in two of our models, they increased frequency of epileptiform discharges in the EC. DHK caused an increase to 140% (50mM) / 161% (300mM) in the low magnesium model; to 155% in the 4-AP model (300mM) and to 496% the penicillin model (300 mM). TBOA (30mM) led to a reduction of discharges to 76% in the low magnesium model and to an increase to 216% in the 4-AP model and to 521% in the penicillin model.

These data show that blocking glutamate uptake in CA1 leads to a suppression of epileptiform activity in two models with enhanced excitation (0 Mg⁺⁺; 4-AP), while discharges following disinhibition (penicillin) are potentiated by DHK and TBOA. These effects differ from findings in the entorhinal cortex where both drugs mostly induced increases in epileptiform activity. The cellular mechanisms underlying the "anticonvulsant" actions of DHK and TBOA may include depletion of excitatory neurons from glutamate or increased inhibitory efficacy due to the increased sequestration of glutamate into inhibitory interneurons. These effects may point towards new therapeutic approaches for the treatment of pharmaco-resistant forms of epilepsy.