mTOR Signaling Pathway in Epileptogenesis

The mechanistic target of rapamycin (mTOR) pathway coordinates cell growth, metabolism and synaptic plasticity in the central nervous system. Dysregulation of mTOR signalling, often through mutations in negative regulators such as PTEN or the tuberous sclerosis complex (TSC1/2), leads to hyperactivation of mTOR complex 1 (mTORC1). Excessive mTORC1 activity alters neuronal morphology, protein synthesis and network organisation, contributing to the initiation and persistence of epileptic circuits. Hyperactive mTOR signalling promotes aberrant dendritic and axonal growth, impairs inhibitory interneuron maturation and disrupts autophagy, thereby lowering seizure threshold and facilitating epileptogenesis. Pharmacological inhibition of mTORC1 with rapamycin or related compounds has been shown to reverse structural abnormalities, restore autophagic flux and reduce seizure frequency in preclinical models. The global significance of mTOR in diverse forms of epilepsy underscores its potential as a unifying therapeutic target to prevent or modify disease progression.

Research from Nature Portfolio

Studies using a neuronal subset-specific PTEN knockout mouse model of cortical dysplasia have revealed a direct link between mTOR hyperactivation and altered expression of the voltage-gated potassium channel Kv1.1. Elevated Kv1.1 protein levels in the hippocampus of adult knockout mice were normalised by rapamycin treatment, indicating mTOR-dependent regulation of ion channel composition and excitability in epileptogenesis. Separately, investigations into neuroprotective treatments for brain injury demonstrated that prolonged administration of insulin-like growth factor 1 (IGF-1) enhances Akt–mTOR signalling and paradoxically exacerbates post-injury epileptogenesis. These findings highlight the dualistic role of anabolic signalling cascades in neuronal survival and seizure susceptibility, emphasising the need for temporally precise modulation of mTOR activity in therapeutic designs.

mTOR Signaling Pathway in Epileptogenesis publication trend

The graph below shows the total number of articles in mtor signaling pathway in epileptogenesis across all publications each year (not limited to Nature Index journals).

Technical terms

mTOR: A serine/threonine kinase that regulates cell growth, metabolism and synaptic plasticity.

mTORC1: A complex containing mTOR that primarily controls protein synthesis and inhibits autophagy.

Epileptogenesis: The process by which a normal brain undergoes structural and functional changes leading to recurrent seizures.

Autophagy: A lysosomal degradation pathway for the removal of damaged proteins and organelles.

Rapamycin: A macrolide compound that selectively inhibits mTORC1 activity.

Voltage-gated potassium channel Kv1.1: A pore-forming subunit that contributes to setting neuronal firing thresholds.

References

1. Autophagy and autophagy signaling in Epilepsy: possible role of autophagy activator. Molecular Medicine (2023).
2. Mechanisms regulating neuronal excitability and seizure development following mTOR pathway hyperactivation. Frontiers in Molecular Neuroscience (2014).
3. Frontier of Epilepsy Research - mTOR signaling pathway. Experimental & Molecular Medicine (2011).
4. mTOR-dependent alterations of Kv1.1 subunit expression in the neuronal subset-specific Pten knockout mouse model of cortical dysplasia with epilepsy. Scientific Reports (2018).
5. Neuroprotective levels of IGF-1 exacerbate epileptogenesis after brain injury. Scientific Reports (2016).