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Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction

Key Points

  • Epileptogenesis is the process whereby a previously normal brain is functionally altered and biased towards the generation of the abnormal paroxysmal electrical activity that defines chronic seizures.

  • The underlying mechanisms that drive epileptogenesis are controversial. It is unlikely that there is a singular mechanism that applies to all epilepsy syndromes.

  • This concept classically refers to the acquired epilepsies but can be viewed as applicable to at least some genetically determined epilepsies as well.

  • Specific themes have emerged in recent years that may represent points of convergence in the field of epileptogenesis, including abnormal signalling by large-scale molecular cascades such as mammalian target of rapamycin and repressor element 1-silencing transcription factor (REST), the dysfunction of particular neuronal cell types with seeming importance in basic mechanisms of epilepsy and dysfunction of discrete neuronal circuit elements.

  • Seizures are by definition circuit-level phenomena that require the re-entrant activation of embedded loop structures within cortical circuits. The above-mentioned considerations further highlight circuit-level considerations and analysis in our future understanding of epileptogenesis and mechanisms of epilepsy.

Abstract

Epilepsy is a prevalent neurological disorder associated with significant morbidity and mortality, but the only available drug therapies target its symptoms rather than the underlying cause. The process that links brain injury or other predisposing factors to the subsequent emergence of epilepsy is termed epileptogenesis. Substantial research has focused on elucidating the mechanisms of epileptogenesis so as to identify more specific targets for intervention, with the hope of preventing epilepsy before seizures emerge. Recent work has yielded important conceptual advances in this field. We suggest that such insights into the mechanisms of epileptogenesis converge at the level of cortical circuit dysfunction.

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Figure 1: Mechanistic roles of the mTOR pathway and REST in epileptogenesis.
Figure 2: Embedded loop structures of the temporal lobe.
Figure 3: Temporal lobe circuit elements under normal conditions.
Figure 4: Circuit dysfunction in temporal lobe epilepsy.

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Acknowledgements

We thank L. Isom, E. Marsh and three anonymous referees for assistance in the preparation of this manuscript.

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Glossary

Dravet syndrome

Previously referred to as severe myoclonic epilepsy of infancy, Dravet syndrome is a spectrum of severe infantile-onset epileptic encephalopathy that is due to an underlying genetic cause, most commonly mutation of the voltage-gated sodium channel subunit NaV1.1. Typically, infants are initially normal, then develop febrile and afebrile seizures, progressing to myoclonus and multiple seizure types, and cognitive impairment.

Circuits

Brain elements that are composed of a collection of neurons of various types and are connected to one another to form a network or ensemble, the operation of which is directed towards a particular function or domain of information processing. Circuits receive inputs, process information and produce outputs.

Tuberous sclerosis

An autosomal dominant multisystem disorder that is caused by a mutation of the tumour suppressor genes tuberous sclerosis complex 1 (TSC1; encoding hamartin) or TSC2 (encoding tuberin). It is accompanied by the characteristic brain lesions of cerebral cortical tubers and subependymal nodules, and by the neurological sequelae of epilepsy, variable intellectual disability and autism.

Mossy fibre sprouting

A process thought to be triggered by cell death of hilar mossy cells, leading to de-innervation of dentate granule cell dendrites, with subsequent 'sprouting' of mossy fibre collaterals and pathological granule cell autoinnervation. Whether this is a cause or consequence of temporal lobe pathology in temporal lobe epilepsy is controversial.

Hemimegalencephaly

A malformation of cortical development that is characterized by the pathological enlargement of one cerebral hemisphere and is highly associated with developmental delay and intractable epilepsy.

Kainate- or pilocarpine-induced status epilepticus

Standard and widely used models of acquired chronic focal epilepsy in rodents in which status epilepticus is elicited via the administration of a chemoconvulsant, either the glutamate agonist kainic acid (kainate) or the muscarinic acetylcholine receptor agonist pilocarpine.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel

An ion channel that is activated by hyperpolarization and mediates a mixed cationic current known as Ih. It has multiple important functions in the regulation of neuronal excitability. HCN channels are encoded by four genes (HCN1–HCN4).

Kindling

A phenomenon whereby seizures themselves contribute to epilepsy progression. The kindling model in experimental animals involves the generation of repeated, brief, focal seizures using electrical or chemical stimulation, which subsequently leads to permanently enhanced sensitivity to such stimuli and longer, more severe seizures, and ultimately to chronic epilepsy.

GABA switch

In the developing brain, GABA is an excitatory neurotransmitter and depolarizes neurons. As the brain matures, a shift in the chloride potential of neurons causes the effects of GABA to become hyperpolarizing and hence inhibitory.

Stratum lacunosum-moleculare

A hippocampal layer that is located superficially relative to the stratum radiatum beneath the pial surface and contains the perforant path input onto distal dendritic tufts of CA1 pyramidal cells.

Stratum radiatum

A hippocampal layer located just superficially relative to the stratum lucidum in area CA3 and to the pyramidal cell layer in areas CA2 and CA1 that contains the Schaffer collateral axons from areas CA3 to CA1 and the dendrites of CA1 pyramidal cells.

Stratum oriens

A relatively cell-free layer in the CA subfields of the hippocampus that is located below the pyramidal cell layer that contains the axons of hippocampal pyramidal cells, along with various types of GABAergic interneurons including oriens-lacunosum moleculare interneurons.

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Goldberg, E., Coulter, D. Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction. Nat Rev Neurosci 14, 337–349 (2013). https://doi.org/10.1038/nrn3482

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