Abstracts

RATIONALE: In humans, seizures disorders during childhood are different from those of adults. They are frequently severe and can induce mental retardation. They are usually observed during a critical developmental period and are therefore age-dependent. They are heterogeneous and some of them are difficult to control because they are resistant to most of the antiepileptic drugs. There is therefore a great need for new drugs in childhood epilepsy, but their optimal development require an animal model with satisfactory clinical relevance.
METHODS: Most of the severe limitations of previous models using slices were avoided using the intact hippocampal formation of postnatal rats (P0-P12). In this preparation that contains the hippocampus, septum and a large part of the cortex, the integrity of the neuronal network between the different areas was preserved (Khalilov et al, Neuron, 1997, 19, 743-749) . Seizures induced by a low concentration of magnesium ions in the superfused ACSF were recorded in the hippocampus (CA1, CA3) and entorhinal cortex using multiple extracellular electrodes.
RESULTS: Only irregular interictal discharges were detected around birth. Both interictal and ictal like seizures (ILEs) were observed from P1-P2 to P10. Between P2 and P6, their frequency and amplitude were developmentally regulated and their duration was stable. ILEs can be generated as long as the low magnesium concentration was maintained. Between P7 and P10, ILEs of longer duration were observed and they were progressively replaced by a new discharge pattern represented by late recurrent discharges (LRDs). This regular interictal activity resembles status epilepticus observed in humans. Finally between P10 and P12, ILEs were occasionally observed and LRDs were generated earlier. The different types of discharges were synchronous in CA1 and entorhinal cortex at every age. ILEs were sensitive to TTX, D-APV, adenosine A1 agonists and Mg ions but not to CNQX. ILEs responded to antiepileptic drugs in a same way as convulsive seizures do in infants: for instance, valproate and benzodiazepines were efficient whereas carbamazepine tended to worsen seizures.
CONCLUSIONS: This model, which allows age-dependent generation of different types of discharges in immature rats might be a first step toward a relevant model of epilepsy of early childhood.