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Rapamycin reveals an mTOR-independent repression of Kv1.1 expression during epileptogenesis
Natasha M Sosanya1, Darrin H Brager2, Sarah Wolfe3
1Center for Learning and Memory, Department of Neuroscience, University of Texas at Austin, USA; Institute for Cell and Molecular Biology, University of Texas at Austin, USA.
Abstract:
Changes in ion channel expression are implicated in the etiology of epilepsy. However, the molecular leading to long-term aberrant expression of ion channels are not well understood. The mechanistic/mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that mediates activity-dependent protein synthesis in neurons. mTOR is overactive in epilepsy, suggesting that excessive protein synthesis may contribute to the neuronal pathology. In contrast, we found that mTOR activity and the microRNA miR-129-5p reduce the expression of the voltage-gated potassium channel Kv1.1 in an animal model of temporal lobe epilepsy (TLE). When mTOR activity is low, Kv1.1 expression is high and the frequency of behavioral seizures is low. However, as behavioral seizure activity rises, mTOR activity increases and Kv1.1 protein levels drop. In CA1 pyramidal neurons, the reduction in Kv1.1 lowers the threshold for action potential firing. Interestingly, blocking mTOR activity with rapamycin reduces behavioral seizures and temporarily keeps Kv1.1 levels elevated. Overtime, seizure activity increases and Kv1.1 protein decreases in all animals, even those treated with rapamycin. Notably, the concentration of miR-129-5p, the negative regulator of Kv1.1 mRNA translation, increases by 21days post-status epilepticus (SE), sustaining Kv1.1 mRNA translational repression. Our results suggest that following kainic-acid induced status epilepticus there are two phases of Kv1.1 repression: (1) an initial mTOR-dependent repression of Kv1.1 that is followed by (2) a miR-129-5p persistent reduction of Kv1.1.
Insights
In temporal lobe epilepsy (TLE), mechanistic/mammalian target of rapamycin (mTOR) and miR-129-5p reduce Kv1.1 expression, lowering seizure thresholds. This study reveals two phases of Kv1.1 repression in epilepsy.
Area of Science:
- Neuroscience
- Molecular Biology
- Epilepsy Research
Background:
- Ion channel dysregulation is linked to epilepsy etiology.
- The molecular mechanisms behind long-term aberrant ion channel expression remain unclear.
- Mechanistic/mammalian target of rapamycin (mTOR) is implicated in epilepsy due to its role in activity-dependent protein synthesis.
Purpose of the Study:
- To investigate the roles of mTOR and microRNA miR-129-5p in regulating Kv1.1 expression in an animal model of temporal lobe epilepsy (TLE).
- To elucidate the molecular mechanisms underlying Kv1.1 repression in epilepsy.
Main Methods:
- Utilized an animal model of kainic-acid induced temporal lobe epilepsy (TLE).
- Measured mTOR activity, Kv1.1 protein levels, and miR-129-5p concentrations.
- Administered rapamycin to block mTOR activity.
- Assessed changes in action potential firing thresholds in CA1 pyramidal neurons.
Main Results:
- mTOR activity and miR-129-5p were found to reduce Kv1.1 expression in TLE.
- Lower mTOR activity correlated with higher Kv1.1 expression and fewer seizures.
- Elevated seizure activity led to increased mTOR activity and decreased Kv1.1 levels.
- miR-129-5p levels increased post-status epilepticus, sustaining Kv1.1 repression.
- Rapamycin treatment temporarily reduced seizures and maintained Kv1.1 levels.
Conclusions:
- Epilepsy involves two distinct phases of Kv1.1 repression: an initial mTOR-dependent phase followed by a persistent miR-129-5p-mediated phase.
- Reduced Kv1.1 expression in CA1 pyramidal neurons lowers the action potential firing threshold, potentially contributing to hyperexcitability in TLE.
- Targeting mTOR and miR-129-5p may offer therapeutic strategies for epilepsy.
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