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Before Epilepsy Unfolds: Finding the epileptogenesis switch

Nature Medicine volume 18, pages 1626–1627 (2012)Cite this article

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One unmet clinical need in epilepsy therapy is to arrest epileptogenesis induced by different precipitating events such as brain injury, gene mutation or undefined causes. This requires the discovery of drugs targeting key etiopathogenic mechanisms underlying the disease's onset and progression. Modeling of epileptogenesis has shown this is a dynamic and progressive process altering cellular connectivity and inducing molecular changes in neurons, glia and endothelial cells of the blood-brain barrier that precede the first clinical seizure. Research for new epilepsy therapies is faced with the vital question of whether the different precipitating events trigger overlapping mechanisms of epileptogenesis, as their identification would permit the development of broad-spectrum, etiology-independent drugs.

The tumor suppressor genes Tsc1 and Tsc2 (tuberous sclerosis 1 and 2), which encode hamartin and tuberin, and their upstream regulators phosphatase and tensin homolog (Pten), Ste20-related kinase adaptor a, and neurofibromin 1 are crucial negative modulators of mTOR. Mutations of these genes in humans result in mTOR hyperactivity and pathologic cellular alterations, with high comorbidity with epilepsy3. The identification of Tsc1 and Tsc2 mutations as causative factors of tuberous sclerosis complex (TSC) drew special attention to the possibility of mTOR dysfunction in epileptogenesis, given that about 80% of people with TSC develop epilepsy2. mTOR signaling is enhanced in cortical tubers, pathological brain lesions of TSC, and in the regions of cytoarchitectural abnormalities of other forms of developmental brain malformations associated with intractable seizures2.

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Figure 1: Pathophysiological cascade of mTOR-dependent events leading to epilepsy development.

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  1. Annamaria Vezzani is in the Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milano, Italy.,

    Annamaria Vezzani

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  1. Annamaria Vezzani
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Correspondence to Annamaria Vezzani.

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Vezzani, A. Before Epilepsy Unfolds: Finding the epileptogenesis switch. Nat Med 18, 1626–1627 (2012). https://doi.org/10.1038/nm.2982

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