Faculty Bibliography

An increased neuronal excitability is one of the most important factors involved in the physiopathology of epileptic states. It may occur via two major routes: an increase in cation inflow, a decreasing cation outflow. The recent discovery that Na+ and Ca2+ inflow may occur through channels that do not inactivate (close) rapidly and that can therefore produce plateau action potentials of great duration, make these conductances quite significant in the generation and maintenance of epilepsy. The presence of excitatory neurotransmitters released either by presynaptic terminal or by glial elements must also be considered. As for the mechanisms that operate by reducing outward cationic flow, a reduction in K+ conductance is mainly involved in membrane depolarization. Other ionic conductances of importance in epileptogenesis will relate most significantly to the reduction in synaptic inhibitory mechanisms, i.e. a reduction of GABAergic or glutaminergic synapses.

The oscillatory properties of the membrane potential in inferior olivary neurones were studied in guinea-pig brain-stem slices maintained in vitro. Intracellular double-ramp current injection at frequencies of 1-20 Hz revealed that inferior olivary neurones tend to fire at two preferred frequencies: 3-6 Hz when the cells were actively depolarized (resting potential less than -50 mV), and 9-12 Hz when they were actively hyperpolarized (resting potential more than -75 mV). In 10% of the experiments spontaneous subthreshold oscillations of the membrane potential were observed. These oscillations, which resembled sinusoidal wave forms and had a frequency of 4-6 Hz and an amplitude of 5-10 mV, occurred synchronously in all cells tested within the slice. These oscillations persisted in the presence of 10(-4) M-tetrodotoxin and were blocked by Ca2+ conductance blockers or by the removal of Ca2+ from the bathing solution. The oscillations were affected by gross extracellular stimulation of the slice but not by intracellular activation of any given neurone. The data indicate that these oscillations reflect the properties of neuronal ensembles comprised of a large number of coupled elements. Similar ensemble oscillation could be induced, in most experiments, by adding harmaline (0.1 mg/ml) and serotonin (10(-4) M) to the bath and could be blocked by bath addition of noradrenaline. Harmaline was found to increase cell excitability by hyperpolarizing the neurones and shifting the inactivation curve for the somatic Ca2+ spike to a more positive membrane potential level. The role inferior olivary oscillations play in the organization of motor coordination is discussed.