mTOR signaling in epilepsy: insights from malformations of cortical development

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Enhanced mammalian target of rapamycin (mTOR) signaling is implicated in focal malformations of cortical development (MCD).
• Mutations in mTOR regulatory genes are linked to epilepsy-associated MCD subtypes like tuberous sclerosis complex and hemimegalencephaly.
• Aberrant mTOR activation during development alters cell size, cortical lamination, and neuronal outgrowth.

Purpose of the Study:

• To explore the role of mTOR signaling in focal MCD.
• To investigate the mechanisms linking mTOR hyperactivation to epileptogenesis.
• To evaluate the therapeutic potential of mTOR inhibitors for MCD-related epilepsy.

Main Methods:

• Review of existing literature on mTOR signaling in MCD.
• Analysis of genetic mutations associated with mTORpathies.
• Examination of evidence regarding mTOR's direct effect on neuronal excitability.
• Summary of clinical trial outcomes for mTOR inhibitors in focal MCD.

Main Results:

• Hyperactivated mTOR signaling is a common feature in focal MCD, termed mTORpathies.
• mTOR plays a critical role in regulating cell growth and development, with its dysregulation leading to cortical malformations.
• Emerging evidence suggests mTOR activation directly increases neuronal excitability, contributing to seizures.
• Clinical trials demonstrate the efficacy of mTOR inhibitors in managing seizures associated with focal MCD.

Conclusions:

• Enhanced mTOR signaling is a key driver of focal MCD and associated epilepsy.
• Targeting mTOR with inhibitors offers a promising therapeutic strategy for treating seizures in patients with focal MCD.