Seizuredependent circuit rearrangements

The mesial temporal structures are interconnected by fibre systems that create the reverberating loop involving entorhinal cortex-dentate gyrus-CA3-CAl (subiculum)-entorhinal cortex. Dreier and Heinemann [52] have developed a technique for preparing in vitro slices including the full circuit and demonstrated that it is necessary and sufficient to sustain persistent epileptic activities.

The most striking evidence of epileptogenic hippocampal plasticity was provided in 1969 by Goddard [53], who demonstrated that repetition of electrical stimulation of the amygdala that initially did not evoke epileptic discharges gradually led to greater seizure susceptibility and then spontaneous seizures, a process named kindling. The discovery of kindling was the starting point for a number of experimental studies aimed at defining the biological basis of epileptogenic plasticity. Another important milestone was established by Sutula et al. [54], who first demonstrated that kindling results in sprouting of a mossy fibre pathway that reorganizes synaptic connections in the dentate gyrus. They observed a similar picture in surgically resected hippocampi from patients with epilepsy [55]. These findings have been confirmed by a number of other investigators, including Babb et al. [56] from whose work Fig. 6.5 has been taken. Mossy fibre sprouting had been previously observed after experimentally induced status epilepticus accompanied by extensive neural damage [57]. However, the kindling experiments demonstrated that repeated brief seizures can induce sprouting in the absence of extensive brain damage [5 8]. In human mesial temporal lobe epilepsy, mossy fibre sprouting is consistently associated with hippocampal sclerosis and cell loss. The degeneration of mossy cells in the hippocampal hilus significantly contributes to the circuitry rearrangement (schematically illustrated in Fig. 6.5 [56]).

Sprouted mossy fibres make ectopic synaptic contacts, and thereby create an excitatory feedback circuit [59-61], The excitatory effect of the aberrant recurrent fibres is further enhanced by the facilitation of NMDA receptor-mediated conductance, which has been demonstrated in dentate granule cells from the surgically excised human epileptic temporal lobe tissue [62], Recurrent axon collaterals also make synaptic contacts with inhibitory interneurones, leading to an enhanced inhibition [63] that, rather than preventing the generation of epileptic discharges, contributes to it by promoting synchrony [64], Although the main dentate granule axon target is CA3, it is not known to what extent the sprouted collaterals of granule axons contribute to the enhanced excitability in postsynaptic neurones inside CA3, or contribute to hyperexcitabil-ity elsewhere in the hippocampal-entorhinal circuit, such as in CA1 [65],

The study of circuit reorganization in mesial temporal lobe epilepsy has provided important insights into its biological basis but a number of questions remain unanswered.

Comparisons of human and animal studies have shown that brief seizures can set in motion a cascade of events leading to sprouting and neosynaptogenesis, which may account for the tendency of mesial temporal lobe epilepsy to progress towards medical intractability. In both humans and experimental animal models of epilepsy kainic- and pilocarpine-induced epilepsy exhibits a bipha-

Pilocarpine Epilepsy

Fig. 6.5 Evidence for circuitry rearrangements in human hippocampus surgically removed from patients with mesial temporal lobe epilepsy and hippocampal sclerosis. Left (a) Coronal section of normal human hippocampus stained with cresyl violet. Dashed line segregates the CA4 pyramidal neurones from thehilus of the dentate gyrus (SG = stratum granulosum). (b) Adjacent section. Magnification of boxed area in (a) stained with the Timm method for heavy metals: the dense stain is strictly limited to the zinc-containing granule cells of polymorph layer (PM), whereas supragranular layer (SG), inner, mesial and outer molecular layers (IML, MML, OML) are completely devoid of staining, (c) The corresponding area from a surgically removed hippocampus of a patient with temporal epilepsy and hippocampal sclerosis shows a second band of zinc-containing axons in the IML. (d) Timm stain puncta in IML from boxed area in (c). (e) Timm stain puncta in SG from boxed area in (c). From [56]. Right: schematic representation of granule axon sprouting in hippocampal sclerosis. The newly formed axon collaterals occupy the inner molecular layer devoid of the mossy fibres due to the degeneration of the hilar mossy cells.

Fig. 6.5 Evidence for circuitry rearrangements in human hippocampus surgically removed from patients with mesial temporal lobe epilepsy and hippocampal sclerosis. Left (a) Coronal section of normal human hippocampus stained with cresyl violet. Dashed line segregates the CA4 pyramidal neurones from thehilus of the dentate gyrus (SG = stratum granulosum). (b) Adjacent section. Magnification of boxed area in (a) stained with the Timm method for heavy metals: the dense stain is strictly limited to the zinc-containing granule cells of polymorph layer (PM), whereas supragranular layer (SG), inner, mesial and outer molecular layers (IML, MML, OML) are completely devoid of staining, (c) The corresponding area from a surgically removed hippocampus of a patient with temporal epilepsy and hippocampal sclerosis shows a second band of zinc-containing axons in the IML. (d) Timm stain puncta in IML from boxed area in (c). (e) Timm stain puncta in SG from boxed area in (c). From [56]. Right: schematic representation of granule axon sprouting in hippocampal sclerosis. The newly formed axon collaterals occupy the inner molecular layer devoid of the mossy fibres due to the degeneration of the hilar mossy cells.

Normal OML

Granule cells

Mossy cells

Sprouting OML IML

Granule cells

sic time course, with a prolonged latent interval between the initial event and the chronic epileptic phase during which the activation of Ca2+-dependent proteases, protein kinase C, Ca2+/calmodulinki-nase systems and immediate early genes [66] promote circuit remodelling. The most frequent antecedent, the clinical history of mesial temporal lobe epilepsy, is a prolonged febrile seizure during the first 2 years of life that can be compared to the status epilepticus induced by kainic acid and pilocarpine in experimental animals. Once established, the aberrant hippocampal circuitry creates a condition of hyperexcitability that leads to chronic epilepsy that is often difficult to treat.

However, this theory is not supported by a number of other observations. First of all, experimental interventions that prevent sprouting do not prevent the acquisition of epileptic properties [67]. Second, although PDS-like discharges can be recorded easily from dentate granule cells in sclerotic hippocampal slices, recordings from the epileptogenic hippocampi of patients indicate that bursting neurones are only rarely encountered and that it is difficult to demonstrate synchrony [68,69]. Third, the role of the putatively seizure-dependent cell loss in determining the sprouting is still unclear, as is the role of excess of zinc caused by the sprouting of zinc-containing mossy fibres upon glutamatergic and GABAergic synaptic transmission [70]. Finally, the relevance of seizure-stimulated neurogenesis in the adult dentate gyrus to human mesial temporal lobe epilepsy [71] remains to be clarified.

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