Abstract
Tuberous sclerosis complex (TSC), caused by heterozygous mutations in TSC1 or TSC2, frequently results in intractable epilepsy. Here, we made use of an inducible Tsc1-knockout mouse model, allowing us to study electrophysiological and molecular changes of Tsc1-induced epileptogenesis over time. We recorded from pyramidal neurons in the hippocampus and somatosensory cortex (L2/L3) and combined this with an analysis of transcriptome changes during epileptogenesis. Deletion of Tsc1 resulted in hippocampus-specific changes in excitability and adaptation, which emerged before seizure onset and progressed over time. All phenotypes were rescued after early treatment with rapamycin, an mTOR inhibitor. Later in epileptogenesis, we observed a hippocampal increase of excitation-to-inhibition ratio. These cellular changes were accompanied by dramatic transcriptional changes, especially after seizure onset. Most of these changes were rescued upon rapamycin treatment. Of the genes encoding ion channels or belonging to the Gene Ontology term action potential, 27 were differentially expressed just before seizure onset, suggesting a potential driving role in epileptogenesis. Our data highlight the complex changes driving epileptogenesis in TSC, including the changed expression of multiple ion channels. Our study emphasizes inhibition of the TSC/mTOR signaling pathway as a promising therapeutic approach to target epilepsy in patients with TSC.
Highlights
Tuberous sclerosis complex (TSC) is a developmental disorder caused by an autosomal mutation in the TSC1 or TSC2 gene, with an estimated incidence of 1 in 6000 [1]
Only 2 days later, a significant increase in the number of action potentials was observed during constant-current injections in Tsc1-Cre+ neurons (2-way repeated measures [RM] ANOVA: F1, 30 = 7.1; P = 0.01; Figure 1, B and D), which became much stronger at 8 days after gene deletion (Figure 1, B and E), a time point when the first mice showed seizures (2-way RM ANOVA: F1, 42 = 17.3; P = 0.0002)
Using our previously designed TSC mouse model, we identified distinct electrophysiological and major transcriptome changes that appeared in the early phases of mTOR-dependent epileptogenesis
Summary
Tuberous sclerosis complex (TSC) is a developmental disorder caused by an autosomal mutation in the TSC1 or TSC2 gene, with an estimated incidence of 1 in 6000 [1]. Characteristic of the disorder is the development of tumor-like lesions in multiple organs, including the brain [2, 3]. Patients with TSC show a variety of neurological problems like autism and epilepsy. Being often medically intractable and occurring early in life, epilepsy drastically lowers the quality of life of patients and their caretakers. The presence of early epilepsy correlates with the severity of autism and intellectual disability [4, 5]. It is conceivable that treatment should start as soon as possible and preferably before seizures are detected to achieve the best outcome in terms of seizure control and neurological symptoms. The mechanism behind the development of epilepsy, a process called epileptogenesis, is currently unknown and needs to be understood to develop more efficient and early administrable pharmacological treatments [6]
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