Epileptiform activity generated by endogenous acetylcholine during blockade of GABAergic inhibition in immature and adult rat hippocampus

Abstract

We tested the effects of the acetylcholinesterase inhibitor eserine (10 μM), an indicator of the activity of endogenous ACh, on the generation of epileptiform discharges during blockade of inhibitory GABA A-mediated potentials by bicuculline (10 μM), in the CA3 area of hippocampal slices from postnatal days 4–20 (P4–P20) immature and adult rats. Eserine provoked or significantly increased the frequency of spontaneous synchronous epileptiform discharges, in 6/22 (27%) P4–P10 slices, 34/35 P11–P20 slices and 18/18 adult slices, an epileptogenic effect. In immature slices, spontaneous discharges showed a stable frequency throughout perfusion with eserine, while in 5/11 adult slices an initial fast frequency was followed by a slower steady-state one. The cholinergic agonist carbachol (CCh, 25 μM) provoked only transient or no spontaneous synchronous discharges in adult slices ( n=8), thus suggesting that massive activation of cholinergic receptors may lead to suppression of epileptiform activity in adult brain. Stimulus-induced excitatory CA3 responses, were depressed by eserine in approximately half of 20 P4–P10, 45 P11–P20 and 11 adult slices. The depression consisted of a decrease in the amplitude, duration, and number of population spikes of the field potentials by about 30%, a minor neuroprotective effect, which did not change with maturation. The different developmental profiles of the epileptogenic and neuroprotective effects of endogenous ACh suggest that they are mediated by different mechanisms. These experiments demonstrate that, endogenous ACh is sufficient to induce epileptogenesis during a decrease or failure of GABAergic inhibition, in both ≥P10 immature and in adult hippocampus. We therefore suggest that clinical or behavioral conditions which raise the concentration of endogenous ACh may lower the threshold to seizures.