Epilepsyan emergent property of neuronal networks

Epileptic discharges typically involve excessively synchronous activity in principal neurones. In experimental focal epilepsy this excessive synchronization is due to the mutual excitation of pyramidal cells in the hippocampus, neocortex, or related areas. The essential idea is of a chain reaction. Areas that are especially prone to epileptic discharges have strong synaptic interconnections between their principal cells (e.g. the pyramidal cells of the CA3 region of the hippocampus or layers 3 and 5 of the neocortex). Activity in a few pyramidal cells can propagate through the synaptic network to recruit the whole population of neurones. Normally this propagation is held in check by inhibitory neurones; if the control mechanism is ineffective then epileptic discharges result. In experimental models the balance of synchronization versus control is compromised by treatments that weaken inhibition (usually by drugs such as bicuculline or picrotoxin), strengthen excitation (incubating brain slices in solutions lacking magnesium ions) or strengthen synaptic potentials in general (4-aminopyridine). Combined experimental and theoretical studies of such models have led to some general principals.(5) Synchronous epileptic discharges will result under the following conditions.

1. Connections between excitatory neurones are divergent, i.e. each connects to more than one postsynaptic excitatory neurone.

2. Connections between excitatory neurones are powerful enough to make their postsynaptic cells fire with a high probability. Precisely how high a probability depends on factors such as the connectivity and size of the network. The 'intrinsic' electrical properties of the neurones are important. Many epilepsy-prone areas have cells with prominent voltage-sensitive calcium currents, which are more prolonged than the classical voltage-sensitive sodium currents of the axonal action potential, and which cause neurones to fire bursts of fast sodium action potentials. Such intrinsic bursts greatly amplify transmission between pyramidal cells.

3. The network is large enough to allow all the neurones to link together. The critical mass for a network where the probability of any two cells being directly connected is 1 per cent, and the probability of one cell exciting its target cells is approximately 50 per cent, works out at about 1000 to 2000 neurones.

These features explain experimental brief epileptic discharges very effectively. The brain contains inhibitory mechanisms, both synaptic (inhibitory postsynaptic potentials, presynaptic inhibition) and intrinsic (voltage- and calcium-sensitive potassium channels), to terminate hypersynchronous discharges. Other mechanisms are needed to overcome the burst-termination mechanisms for the crucial transition to full-blown seizures lasting tens of seconds to minutes. These include slower synaptic mechanisms (both N-methyl-D-aspartate and metabotropic glutamate receptors, GABA, which paradoxically can become depolarizing if present in excess), non-synaptic mechanisms (potassium accumulation, electric fields(6)), and abnormal activity arising in axons (ectopic spikes, gap junctions).(5)

Convulsant drugs can trigger seizures in normal brains, including those of humans. People with epilepsy have a reduced seizure threshold. The reasons are far from clear, but may include abnormalities in intrinsic properties of neurones or in the connectivity of the neurones. Improvements in non-invasive imaging and in neuropathology increasingly reveal misplaced neurones and other more or less subtle anatomical malformations in many focal epilepsies, which suggests that the local circuitry is disturbed.

Other kinds of epilepsy have very different mechanisms. Absence epilepsy is the other major class where cellular mechanisms are relatively well understood. They involve the interaction of the thalamus and neocortex, although the received wisdom on the underlying mechanism has recently been challenged by experiments on one of the key animal models of absence epilepsy.(7)

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