TORC1-dependent epilepsy caused by acute biallelic Tsc1 deletion in adult mice

• Published in: Annals of neurology 2013-10, Vol.74 (4), p.569-579
• Main Authors: Abs, Elisabeth, Goorden, Susanna M. I., Schreiber, Jadwiga, Overwater, Iris E., Hoogeveen-Westerveld, Marianne, Bruinsma, Caroline F., Aganović, Elvedin, Borgesius, Nils Z., Nellist, Mark, Elgersma, Ype
• Format: Article
• Language: English
• Subjects: Animals; Carrier Proteins - genetics; Carrier Proteins - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy; Epilepsy - genetics; Epilepsy - metabolism; Epilepsy - pathology; Epilepsy - therapy; Gene Expression Regulation - genetics; Hippocampus - pathology; Immunosuppressive Agents - therapeutic use; Long-Term Potentiation - drug effects; Long-Term Potentiation - genetics; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Transgenic; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Neurons - drug effects; Neurons - metabolism; Neurons - physiology; Pathology; ras Proteins - metabolism; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Rodents; Sequence Deletion - genetics; Sirolimus - therapeutic use; Studies; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Tumor Suppressor Proteins - genetics
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.23943

Objective Seizure development in tuberous sclerosis complex (TSC) correlates with the presence of specific lesions called cortical tubers. Moreover, heterozygous TSC animal models do not show gross brain pathology and are seizure‐free, suggesting that such pathology is a prerequisite for the development of epilepsy. However, cells within TSC lesions show increased activity of the target of rapamycin complex 1 (TORC1) pathway, and recent studies have implicated this pathway in non–TSC‐related animal models of epilepsy and neuronal excitability. These findings imply a direct role for TORC1 in epilepsy. Here, we investigate the effect of increased TORC1 signaling induced by acute biallelic deletion of Tsc1 in healthy adult mice. Methods Biallelic Tsc1 gene deletion was induced in adult Tsc1 heterozygous and wild‐type mice. Seizures were monitored by electroencephalographic and video recordings. Molecular and cellular changes were investigated by Western blot analysis, immunohistochemistry, and electrophysiology. Results Mice developed epilepsy a few days after biallelic Tsc1 deletion. Acute gene deletion was not accompanied by any obvious histological changes, but resulted in activation of the TORC1 pathway, enhanced neuronal excitability, and a decreased threshold for protein‐synthesis–dependent long‐term potentiation preceding the onset of seizures. Rapamycin treatment after seizure onset reduced TORC1 activity and fully abolished the seizures. Interpretation Our data indicate a direct role for TORC1 signaling in epilepsy development, even in the absence of major brain pathology. This suggests that TORC1 is a promising target for treating seizures not only in TSC but also in other forms of epilepsy that result from increased TORC1 activation. Ann Neurol 2013;74:569–579