Effects of antiepileptic drugs in a new TSC/mTOR‐dependent epilepsy mouse model

Abstract

Objective An epilepsy mouse model for Tuberous Sclerosis Complex (TSC) was developed and validated to investigate the mechanisms underlying epileptogenesis. Furthermore, the possible antiepileptogenic properties of commonly used antiepileptic drugs (AEDs) and new compounds were assessed. Methods Tsc1 deletion was induced in CAMK2A‐expressing neurons of adult mice. The antiepileptogenic properties of commonly used AEDs and inhibitors of the mTOR pathways were assessed by EEG recordings and by molecular read outs. Results Mice developed epilepsy in a narrow time window (10 ± 2 days) upon Tsc1 gene deletion. Seizure frequency but not duration increased over time. Seizures were lethal within 18 days, were unpredictable, and did not correlate to seizure onset, length or frequency, reminiscent of sudden unexpected death in epilepsy (SUDEP). Tsc1 gene deletion resulted in a strong activation of the mTORC1 pathway, and both epileptogenesis and lethality could be entirely prevented by RHEB1 gene deletion or rapamycin treatment. However, other inhibitors of the mTOR pathway such as AZD8055 and PF4708671 were ineffective. Except for ketogenic diet, none of commonly used AEDs showed an effect on mTORC1 activity. Vigabatrin and ketogenic diet treatment were able to significantly delay seizure onset. In contrast, survival was shortened by lamotrigine. Interpretation This novel Tsc1 mouse model is highly suitable to assess the efficacy of antiepileptic and ‐epileptogenic drugs to treat mTORC1‐dependent epilepsy. Additionally, it allows us to study the mechanisms underlying mTORC1‐mediated epileptogenesis and SUDEP. We found that early treatment with vigabatrin was not able to prevent epilepsy, but significantly delayed seizure onset.

Laser microdissection-based microproteomics of the hippocampus of a rat epilepsy model reveals regional differences in protein abundances

“…All these changes, together with the enrichment of the mTORC2 downstream signalling pathway, suggest that abnormal expression of PARK7 and GAP-43 might be a result of the dysregulation of the mTOR pathway in the PPS model. Indeed, the mTOR pathway has been shown to be involved in many neurological disorders, such as autism spectrum disorders 47,48 , Alzheimer's disease, tuberous sclerosis complex 46,49,50 , focal cortical dysplasia 51,52 and, more recently, intractable epilepsy 49,[53][54][55][56][57][58] . The mTORC1 and mTORC2 complexes are also upregulated in tissue from patients with MTLE 59 .…”

Proteomics for Studying the Effects of Ketogenic Diet Against Lithium Chloride/Pilocarpine Induced Epilepsy in Rats

“…The ketogenic diet (KD) is a high fat, low carbohydrate regime widely considered an effective non-drug treatment for epilepsy with documented anticonvulsant, antiepileptogenic, and neuroprotective effects on clinically refractory epilepsy and animal models of epilepsy ( Lusardi et al, 2015 ; Simeone et al, 2018 ; Karimzadeh et al, 2019 ). Multiple therapeutic mechanisms have been proposed for KD-induced antiepileptogenesis, including increased adenosine and decreased DNA methylation, reduced mTORC1 activity, and blockade of histone deacetylases ( Koene et al, 2019 ; Boison and Rho, 2020 ). Thus, it is critical to comprehensively assess the molecular changes associated with the KD in epilepsy.…”

Tuberous sclerosis‐associated epilepsy and intellectual disability: what role does the mammalian target of rapamycin pathway play?

“…2 Recently, preclinical evidence suggested that epilepsy severity is directly related to the level of neuronal mTORC1 activity. 5 In a TSC/mTOR-dependent epilepsy mouse model, early treatment with vigabatrin was not able to prevent epileptogenesis, but significantly delayed seizure onset. However, in this preclinical model, epileptogenesis driven by the loss of TSC1 showed a dose-dependent response to the mTORC1 inhibitor, rapamycin.…”

“…A longitudinal study showed that a cascading risk pathway from gene mutation to cortical tubers and seizure severity in infancy, to poor intellectual outcome in late childhood can be a potential pathogenic mechanism . Recently, preclinical evidence suggested that epilepsy severity is directly related to the level of neuronal mTORC1 activity . In a TSC/mTOR‐dependent epilepsy mouse model, early treatment with vigabatrin was not able to prevent epileptogenesis, but significantly delayed seizure onset.…”

“…However, in this preclinical model, epileptogenesis driven by the loss of TSC1 showed a dose-dependent response to the mTORC1 inhibitor, rapamycin. 5 mTOR cascade can be a potential hidden major cause of TSC-associated epilepsy and intellectual disability. Additional research should investigate if early suppression of an abnormal mTOR signal with mTOR inhibitors before the occurrence of seizures can be a more efficient approach and an effective antiepileptogenic and disease-modifying strategy in infants with TSC.…”