Abstracts

Despite lower synaptic connectivity, the immature brain is much more susceptible to seizures than the adult brain and ictal epileptiform activity can be elicited easily in the developing rat hippocampus [italic]in vitro[/italic] during the first three postnatal weeks. Modeling studies clearly indicate that synchronous activity is not easily maintained when synaptic connectivity is low. Thus, there must be a compelling proconvulsant factor or factors that increase epileptiform activity propensity in the immature brain.
Hippocampal slices were prepared from male Wistar rats at the postnatal day 1 (P1) to P40. Whole-cell and extracellular field potential recordings were performed in the CA3 pyramidal cell layer. Use of tungsten microelectrodes enables simultaneous recordings of multiple-unit activity (MUA, 500 Hz high-pass filter) and population field activity (EEG band, 1-100 Hz) from tens to hundreds of neurones near each electrode.
We studied the generation and pharmocology of elevated extracellular potassium (8.5 mM) induced epileptiform activity in the hippocampal slices of the immature (P1-P40) rat [italic]in vitro. [/italic]The interictal epileptiform discharges (IED) were more than twice higher in frequency during the first three postnatal weeks as in slices from the older rats and this period was characterized by prolonged recurrent ictal-like epileptiform activity (70 % of slices). We assesed the effects of endogenously released GABA on epileptiform patterns and neuronal firing rate in this developmental window. There was a strong correlation between the postnatal age at which ictal activity could be induced by elevated potassium and the age at which GABA[sub]A[/sub]-R antagonists decreased action potential frequency when excitatory ionotropic receptors were blocked. In addition, there was a strong correlation between the fraction of slices in which ictal activity was induced by elevated potassium concentrations and the fractional decrease in action potential firing when GABA[sub]A[/sub]-Rs were blocked in the presence of ionotropic glutamate receptor antagonists. During the first three postnatal weeks, the frequency of IEDs was decreased 5 to 10 fold following blockade of GABA[sub]A[/sub]-Rs. Finally, ictal-like epileptiform activity was blocked by the GABA[sub]A[/sub]-R antagonists bicuculline and (SR-95531) gabazine and increased in frequency and duration by GABA[sub]A[/sub]-R agonists isoguvacine and muscimol.
The propensity of the developing hippocampus for epileptiform patterns is highly correlated with the effect of GABA agonists and antagonists on action potential probability and IED frequency, indicating that GABA-mediated excitation is causally linked to epileptiform activity in this developmental window.
[Supported by: a grant from the National Institutes of Health, National Institute of Neurological Disorders and Stroke]