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Rapamycin down-regulates KCC2 expression and increases seizure susceptibility to convulsants in immature rats
1Center for Neuropharmacology and Neuroscience, Albany Medical College, NY 12208, USA.
Abstract:
Seizure susceptibility to neurological insults, including chemical convulsants, is age-dependent and most likely reflective of overall differences in brain excitability. The molecular and cellular mechanisms underlying development-dependent seizure susceptibility remain to be fully understood. Because the mammalian target of rapamycin (mTOR) pathway regulates neurite outgrowth, synaptic plasticity and cell survival, thereby influencing brain development, we tested if exposure of the immature brain to the mTOR inhibitor rapamycin changes seizure susceptibility to neurological insults. We found that inhibition of mTOR by rapamycin in immature rats (3-4 weeks old) increases the severity of seizures induced by pilocarpine, including lengthening the total seizure duration and reducing the latency to the onset of seizures. Rapamycin also reduces the minimal dose of pentylenetetrazol (PTZ) necessary to induce clonic seizures. However, in mature rats, rapamycin does not significantly change the seizure sensitivity to pilocarpine and PTZ. Likewise, kainate sensitivity was not significantly affected by rapamycin treatment in either mature or immature rats. Additionally, rapamycin treatment down-regulates the expression of potassium-chloride cotransporter 2 (KCC2) in the thalamus and to a lesser degree in the hippocampus. Pharmacological inhibition of thalamic mTOR or KCC2 increases susceptibility to pilocarpine-induced seizure in immature rats. Thus, our study suggests a role for the mTOR pathway in age-dependent seizure susceptibility.
Insights
Inhibition of the mammalian target of rapamycin (mTOR) pathway in immature rats increases seizure susceptibility to chemical convulsants. This suggests a role for mTOR in age-dependent seizure development.
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Molecular Neuroscience
Background:
- Seizure susceptibility to neurological insults exhibits age-dependent patterns, reflecting developmental changes in brain excitability.
- The precise molecular mechanisms underlying these age-dependent differences in seizure susceptibility are not fully elucidated.
- The mammalian target of rapamycin (mTOR) pathway is crucial for regulating neurite outgrowth, synaptic plasticity, and cell survival during brain development.
Purpose of the Study:
- To investigate the impact of inhibiting the mTOR pathway with rapamycin on seizure susceptibility in immature versus mature rats.
- To explore the role of mTOR signaling in age-dependent alterations of brain excitability and seizure vulnerability.
Main Methods:
- Immature (3-4 weeks old) and mature rats were treated with rapamycin, an mTOR inhibitor.
- Seizure susceptibility was assessed using chemical convulsants such as pilocarpine and pentylenetetrazol (PTZ).
- Expression levels of potassium-chloride cotransporter 2 (KCC2) in the thalamus and hippocampus were analyzed post-treatment.
- Pharmacological inhibition of thalamic mTOR and KCC2 was performed to confirm their roles.
Main Results:
- Rapamycin treatment significantly increased seizure severity and duration in immature rats, while reducing seizure onset latency.
- The minimal effective dose of PTZ to induce seizures was lowered in immature rats treated with rapamycin.
- In contrast, rapamycin did not significantly alter seizure sensitivity to pilocarpine or PTZ in mature rats.
- Kainate-induced seizure sensitivity remained unaffected by rapamycin in both age groups.
- Rapamycin treatment led to down-regulation of KCC2 expression in the thalamus and hippocampus of immature rats.
- Pharmacological inhibition of thalamic mTOR or KCC2 exacerbated pilocarpine-induced seizures in immature rats.
Conclusions:
- The mammalian target of rapamycin (mTOR) pathway plays a significant role in modulating age-dependent seizure susceptibility.
- Inhibition of mTOR in the immature brain enhances vulnerability to seizures, potentially through mechanisms involving KCC2 down-regulation in the thalamus.
- These findings highlight the mTOR pathway as a potential therapeutic target for age-related seizure disorders.
