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Chapter 3

Basic mechanisms of epilepsy

JOHN G.R. JEFFERYS

Department of Pharmacology, University of Oxford

Epileptic seizures typically involve excessive firing and synchronisation of neurons. This
interrupts the normal working of the parts of the brain involved, leading to the clinical
symptoms and semiology of the specific type of epilepsy. This chapter will outline basic
mechanisms of epileptic discharges, particularly in terms of the cellular electrophysiology of
focal epilepsies. It will outline recent advances in clarifying the concept of
‘hypersynchronous’ neuronal activity during seizures.

Focal epileptic activity

Focal epilepsies arise in the neocortex and limbic structures including hippocampus and
amygdala. Work on a range of experimental models produced detailed theories on the
generation of brief (~100500 ms) epileptic events analogous to the ‘inter-ictal spikes’ often
found in the EEGs of humans with focal epilepsy. Experimental inter-ictal discharges are
characterised by abrupt ‘paroxysmal’ depolarisation shifts (PDSs) that occur synchronously
in the majority of neurons in the local area. These are large depolarisations, 2040 mV, which
make the neurons fire rapid bursts of action potentials. The PDS has properties of a giant
excitatory postsynaptic potential (EPSP), and depends on glutamate, which is the main
excitatory synaptic transmitter in the brain. This giant EPSP is driven by the simultaneous
excitation from many other neurons within the same population. The PDS also depends on
the intrinsic properties of the soma-dendrite regions of the neurons, for instance voltage-
sensitive calcium channels can produce slow depolarisations that drive multiple fast (sodium
channel) action potentials.

Combined experimental and theoretical work on many experimental models show that the
following features are sufficient for this kind of epileptic discharge:

 Excitatory (usually pyramidal) neurons must make divergent connections into a synaptic
network. The probability of such connections can be quite low  for instance between
~12% of randomly-chosen pairs of pyramidal cells in the hippocampus.

 The synapses need to be strong enough, because of the properties of the individual
synapses and/or because of the firing patterns of the presynaptic neurons (burst firing due
to slower voltage-sensitive depolarising channels means that synaptic potentials can
summate). Essentially neurons need to have a good chance of driving their postsynaptic
targets above threshold.

 The population of neurons must be large enough (the ‘minimum aggregate’  analogous
to the critical mass of a nuclear fission bomb). This minimum aggregate allows neurons
to connect with almost all the others in the population within a few synapses, with the
result that activity in a small subset of neurons can spread through the population very
rapidly under the right conditions. The divergent connections mean that the neuronal
population is recruited in a near-geometrical progression. In experimental models the
minimum epileptic aggregate can be as low as 10002000 neurons, but is probably larger
in human epileptic foci.