Epilepsies and neuronal plasticity: for better or for worse?

Abstract

Extensive experimental investigations have confirmed that "seizures beget seizures." Thus, in adults, limbic seizures lead to cell loss, followed by the formation of novel excitatory synapses that contribute to generating further seizures. The triggering signal is an enhancement of synaptic efficacy, followed by a molecular cascade that triggers axonal sprouting. New synapses are aberrant, since they are formed in regions in which they are not present in controls. They also involve receptors that are not present in controls, and this facilitates the generation of seizures. Therefore, an aberrant form of reactive neuronal plasticity provides a substrate for the long-lasting sequelae of seizures. Since these events take place in brain structures involved in integrative and mnemonic functions, they will have an important impact. Reactive plasticity is documented for other insults and disorders, and may be the basis for the long-term progression of neurodegenerative disorders.

Figure 1.. Sprouting of fibers in the hippocampus of epileptic rats. Morphological reconstruction of CA1hippocampal neurons intracellular/ injected with dyes weeks after an inaugurating status epilepticus. Note the extensive sprouting of axons, including to layers (the molecular layers) that are not innervated by pyramidal axons in controls. 0, stratum oriens; P, stratum pyramidale; R; stratum radiatum; S, subiculum Reproduced from ref 44: Esclapez M, Hirsch JC, Ben Ari Y, Bernard C. Newly formed excitatory pathways provide a substrate for hyperexcitabi I ity in experimental temporal lobe epilepsy. J Comp Neurol. 1999;408:449-460. Copyright © Wiley-Liss 1999

Figure 2.. Electron microscopic identification of aberrant mossy fiber terminals on granule cells weeks after an inaugurating status. Note the formation of synapses in regions that are not innervated by mossy fibers in controls. These aberrant synapses have all the typical unique features of mossy fiber terminals, notably the large size and the enrichment in vesicles. D: Left and right columns show the upper and lower blades of the granular cell layer. Reproduced from ref 45: Represa A, Pollard H, Moreau J, Ghilini G, Khrestchatisky M, Ben-Ari Y. Mossy fiber sprouting in epileptic rats is associated with a transient increased expression of alpha-tubulin. Neurosci Lett. 1993;156:149-152. Copyright © Elsevier Scientific Publishers ireland 1993

Figure 3.. Increased kainate receptors binding in regions innervated by aberrant mossy fibers. There is an increased density of receptors thirty days, but not 12 days, after an inaugurating status. The latency correlates with the time needed to form novel synapses. Reproduced from ref 19: Represa A, Tremblay E, Ben-Ari Y Kainate binding sites in the hippocampal mossy fibers: localization and plasticity. Neuroscience. 1987;20:739-748. Copyright © Elsevier Science 1987

Figure 4.. Enhanced glutamatergic activity in epileptic hippocampus weeks after the inaugurating event. Slices were prepared from rats 4 weeks after the status produced by a single injection of pilocarpine. Note the considerable increase of spontaneous glutamatergic activity in the epileptic hippocampus (right side) versus a control slice (left). A: control; B: epileptic; C: The bottom left column illustrates the increase quantitatively (in frequency of glutamate EPSCs). The right columns show a similar increase in the miniature PSCs recorded after applications of tetrodoxin (TTX) to block activity-dependent currents. This suggests a longlasting increase in quantal release of transmitter in the epileptic network. EPSCs, excitatory postsynaptic currents; PSCs, postsynaptic currents

Figure 5.. Seizures beget seizures in the immature hippocampus. A: A triple chamber is used (top left) with three compartments that accommodate each intact hippocampus and the connecting commissural connections. B: When the powerful convulsive agent kainate is applied, epileptiform activities are generated in the treated side and propagate rapidly to the naive side (top left). C: After repeated applications and seizure propagation to the naive side, tetrodoxin (TTX) a blocker of action potentials and of the propagation of seizures, was applied to the commissural chamber and effectively blocked seizures. Note (bottom part) that seizures were generated spontaneously by the naive hippocampus after disconnection form the treated side: there is formation of an epileptogenic mirror focus.