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time. Chronic experimental models, and where it is possible to make the appropriate
measurements in human localisation-related epilepsies, reveal multiple changes in the
structure and function of the neuronal networks. Some of the better characterised include:

 Increased synaptic connectivity. The best known example is mossy fibre sprouting,
where the axons of the granule cells of the hippocampal dentate area, which normally
are restricted to the hilus and parts of CA3, but in temporal lobe epilepsy invade the
molecular layer above the granule cell body layer. Other axons are more difficult to
assess, but sprouting does occur in at least some cases. At least in theory, this will
promote the chain reaction recruitment of excitatory, glutamatergic neurons outlined
above, although their additional synapses onto interneurons complicate the
pathophysiology.

 Intrinsic properties. Voltage-gated ion channels change in many epilepsies. This is very
clear in the small minority of epilepsies that are genetic channelopathies: in some,
potassium channels are weakened, in others sodium channels may become more
persistent. In these cases the mutation is presumably a primary factor in epileptogenesis.
Changes in voltage-gated ion channels also can be found in much more common
epilepsies that do not have an obvious genetic basis, for instance temporal lobe epilepsy
where sodium channel inactivation is delayed leading to increases in persistent sodium
currents (often in parallel with a loss of sensitivity to carbamazepine).

 Synaptic receptors can also be abnormal in epileptic tissue. Again the inherited
channelopathies have good examples of altered GABAergic receptors (tending to
depress inhibitory potentials), and of changes in nicotinic receptors. Other studies of
more common idiopathic epilepsies reveal alterations in expression of specific receptor
subunits.

 Inhibitory transmission may be altered in more subtle ways than changes in receptors,
such as: changes in chloride homeostasis (specifically chloride transporters) which can
make IPSPs depolarising instead of hyperpolarising, changes in the responsiveness of
interneurons to excitatory input, or selective losses of particular classes of interneuron.

Inter-ictal discharges versus seizures. While inter-ictal discharges are commonly associated
with localisation-related epilepsy, they are probably generated by different, or at least non-
identical, circuits from those responsible for seizure initiation. Moreover, the role of inter-
ictal discharges in seizure generation is far from clear. Results from some experimental
models suggest that they may help prevent prolonged seizures getting started, by mechanisms
yet to be determined. Other studies suggest that inter-ictal discharges may come in more than
one variety, some of which tend to precipitate seizures; these seizure-promoting inter-ictal
discharges typically have a large GABAergic component and lead to relatively large increases
in extracellular potassium concentrations, maybe prolonging the epileptic activity into the
early stages of a seizure. However, much remains to be discovered on the precise mechanisms
that sustain seizures, and that usually terminate them within a couple of minutes.

Hypersynchrony. Recently the long-standing concept of epileptic seizures as
hypersynchronous events has been challenged. One issue is the definition of synchronous:
the Oxford English Dictionary version is ‘existing or happening at the same time’. The
criticism here is that not much in biology happens at exactly the same time. Other terms may
be more precise but are not in widespread use, so a degree of imprecision in the use of
language may be better, at least for the time being.