Psychiatric diseases 10101 Epilepsy

Epilepsy results from abnormal synchrony in the neuronal networks, when many nerve cells start to fire simultaneously. These discharges can be visualized on the EEG, which reveals cortical spikes and sharp waves. The cellular substrate of epilepsy is a slow depolarization of neurones, which occurs without any apparent provocation and develops synchronously in virtually all nerve cells within the epileptic foci. This slow neuronal depolarization is known as paroxysmal depolarization shift, PDS.

The PDS results from large excitatory postsynaptic potentials, which develop slower than normal EPSPs, triggered by electrical excitation of incoming synaptic terminals; usually the PDS lasts from 50 to 200 ms. The synaptic potential underlying the PDS is mediated by glutamate receptors of AMPA and NMDA types, and is caused by simultaneous glutamate release around many neurones comprising epileptic foci. When the PDS fails to terminate, the prolonged synchronous depolarization of many neurones results in seizures, which are the hallmarks of epilepsy.

Astrocytes begin to be involved in pathogenesis of epilepsy at very early stages of the disease; they become reactive, they are hypertrophied, change their shape and increase in number and this reactive astrogliosis occurs before any neurode-generative changes and even before the appearance of fully developed seizures. Physiologically, neuronal PSD and seizures lead to depolarization of astrocytes surrounding the epileptic zone.

Very recently it has become apparent that PSD can still develop in conditions of synaptic isolation - i.e. when neuronal firing is completely blocked by tetrodotoxin, which effectively poisons Na+ channels. Moreover, it was also shown that local stimulation of astroglial [Ca2+]j signals in brain slices prepared from hippocampus can trigger release of glutamate, which in turn initiates PSD and epileptiform discharges in neighbouring neurones. Moreover, glial [Ca2+]i waves always preceded spontaneous PSD in the brains of animals experimentally made epileptic.

This new knowledge about the role of astrocytes in producing neuronal epilepti-form activity will considerably change our understanding of epilepsy pathogenesis. In fact, the introduction of astrocytes into the epileptic circuit (Figure 10.9) can be instrumental in describing the most enigmatic property of the epileptic brain -i.e. the precise synchronization between many neurones. This synchronization may result, for example, from abnormal glutamate release from an individual astrocyte, which can reach up to 100 000 synapses within the astroglial domain,

Pathogenesis Epilepsy Seizure

Figure 10.9 Astroglia and epileptic seizures. Astroglial calcium waves may trigger synchronous release of glutamate, which in turn may act simultaneously on many neurones and trigger the specific depolarization, the paroxysmal depolarization shift, considered to be the electrical correlate of epileptic seizure

Figure 10.9 Astroglia and epileptic seizures. Astroglial calcium waves may trigger synchronous release of glutamate, which in turn may act simultaneously on many neurones and trigger the specific depolarization, the paroxysmal depolarization shift, considered to be the electrical correlate of epileptic seizure virtually simultaneously. Furthermore, several astroglial cells can work as a single unit, being synchronized through gap junctions, and then the number of neurones affected by one simultaneous glutamate discharge can be much greater. These new insights into the pathology of epilepsy may also considerably modify the quest for new therapeutic strategies, as astroglial cells may well be the primary target. Incidentally, several anti-epileptic drugs, including valproate, gabapentin and phenytoin, are able to inhibit astroglial Ca2+ signalling, which may, at least in part, account for their anticonvulsant potency.

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