Exploration of Neuroscience (Oct 2024)
Somatostatin-expressing inhibitory neurons with mTORC1 activation in cortical layers 4/5 are involved in the epileptogenesis of mice
Abstract
Aim: Patients with tuberous sclerosis complex (TSC) which is caused by hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) often show giant cells in the brain. These giant cells are thought to be involved in epileptogenesis, but the underlying mechanisms are unknown. In this study, we focused on mTORC1 activation and γ-amino butyric acid (GABA)ergic signaling in somatostatin-expressing inhibitory neurons (SST-INs) using TSC-related epilepsy model mice. Methods: We analyzed the 8-week-old Tsc2 conditional knockout (Tsc2 cKO) mice, which have epileptic seizures that are cured by sirolimus, an mTORC1 inhibitor. After the occurrence of epileptic seizures was confirmed, Tsc2 cKO mice were treated with vehicle or sirolimus. Then, their brains were investigated by hematoxylin and eosin staining, immunohistochemical staining and immunoblotting assay. Results: As in TSC patients, giant cells with hyperactivation of mTORC1 were found in the cerebral cortex of Tsc2 cKO mice. These giant cells were mainly SST-INs in the cortical layers 4/5. Giant cells showed decreased expression of GABA type A receptor subunit α1 (GABAAR-α1) compared with normal size cells in control mice and Tsc2 cKO mice. In addition, decreased GABAAR-α1 expression was also confirmed by immunoblotting assay of the whole cerebral cortex. In the cerebral cortex of sirolimus-treated Tsc2 cKO mice, whose epileptic seizures were cured, decreased GABAAR-α1 expression was recovered to the same level as in control mice. Conclusions: These results suggest that the epileptic seizures in Tsc2 cKO mice are caused by the deregulation of GABAergic signaling through mTORC1 activation of SST-INs localized in cortical layers 4/5.
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