Abstract
Epileptogenesis is a process triggered by initial environmental or genetic factors that result in epilepsy and may continue during disease progression. Important parts of this process include changes in transcriptome and the pathological rewiring of neuronal circuits that involves changes in neuronal morphology. Mammalian/mechanistic target of rapamycin (mTOR) is upregulated by proconvulsive drugs, e.g., kainic acid, and is needed for progression of epileptogenesis, but molecular aspects of its contribution are not fully understood. Since mTOR can modulate transcription, we tested if rapamycin, an mTOR complex 1 inhibitor, affects kainic acid-evoked transcriptome changes. Using microarray technology, we showed that rapamycin inhibits the kainic acid-induced expression of multiple functionally heterogeneous genes. We further focused on engulfment and cell motility 1 (Elmo1), which is a modulator of actin dynamics and therefore could contribute to pathological rewiring of neuronal circuits during epileptogenesis. We showed that prolonged overexpression of Elmo1 in cultured hippocampal neurons increased axonal growth, decreased dendritic spine density, and affected their shape. In conclusion, data presented herein show that increased mTORC1 activity in response to kainic acid has no global effect on gene expression. Instead, our findings suggest that mTORC1 inhibition may affect development of epilepsy, by modulating expression of specific subset of genes, including Elmo1, and point to a potential role for Elmo1 in morphological changes that accompany epileptogenesis.
Highlights
Epilepsy is a common chronic neurological disorder that is characterized by recurrent seizures that are unpredictable and sometimes progressively severe [1]
We investigated the effects of rapamycin on kainic acid (KA)-induced changes in the KA in rat hippocampal slices and validation of selected gene expression changes. a Microarray results are shown as a heat map and include rat genes with genome-wide significance
We used a simplified in vitro culture system to investigate whether rapamycin affects transcriptome changes that are evoked by KA
Summary
Epilepsy is a common chronic neurological disorder that is characterized by recurrent seizures that are unpredictable and sometimes progressively severe [1]. Epilepsy is triggered by various environmental and genetic factors [2, 3] that induce numerous molecular changes, including changes in gene expression, that drive epileptogenesis [4, 5]. Several lines of evidence suggest links between epileptogenesis and complex 1 of mammalian/mechanistic target of rapamycin (mTOR), a serine-threonine protein kinase [8, 9]. Status epilepticus induces mTOR activation [10,11,12,13]. Rapamycin, an mTOR inhibitor, has antiepileptogenic effects in kainic acid (KA)-induced and pilocarpine-induced models of epilepsy in animals [13,14,15]. MTOR complex 1 (mTORC1) is known to control the transcription of several genes [16]. Our previous studies found increased nuclear levels of phosphorylated mTOR in hippocampal and cortical neurons cultured in vitro and in the brain in vivo after
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