Abstract
Epilepsy is characterized by recurrent, spontaneous seizures and is a major contributor to the global burden of neurological disease. Although epilepsy can result from a variety of brain insults, in many cases the cause is unknown and, in a significant proportion of cases, seizures cannot be controlled by available treatments. Understanding the molecular alterations that underlie or are triggered by epileptogenesis would help to identify therapeutics to prevent or control progression to epilepsy. To this end, the moderate throughput technique of Reverse Phase Protein Arrays (RPPA) was used to profile changes in protein expression in a pilocarpine mouse model of acquired epilepsy. Levels of 54 proteins, comprising phosphorylation-dependent and phosphorylation-independent components of major signaling pathways and cellular complexes, were measured in hippocampus, cortex and cerebellum of mice at six time points, spanning 15 min to 2 weeks after induction of status epilepticus. Results illustrate the time dependence of levels of the commonly studied MTOR pathway component, pS6, and show, for the first time, detailed responses during epileptogenesis of multiple components of the MTOR, MAPK, JAK/STAT and apoptosis pathways, NMDA receptors, and additional cellular complexes. Also noted are time- and brain region- specific changes in correlations among levels of functionally related proteins affecting both neurons and glia. While hippocampus and cortex are primary areas studied in pilocarpine-induced epilepsy, cerebellum also shows significant time-dependent molecular responses.
Highlights
Epilepsy affects more than 65 million people worldwide, making it the third most common neurological disorder [1]
Levels of 54 proteins were measured in hippocampus, cortex and cerebellum, at six time points after pilocarpine injection: at ∼15 min, at 1, 6, and 24 h, at 5 days, and at 2 weeks
All values are significant as determined by a three-level mixed effects model, with p ≤ 0.005 and the Benjamini-Hochberg correction for multiple testing, with false discovery rate (FDR) p ≤ 0.05
Summary
Epilepsy affects more than 65 million people worldwide, making it the third most common neurological disorder [1]. While some cases of epilepsy have a known genetic basis, others, the acquired epilepsies, arise from brain insults, such as traumatic injury, inflammation, tumor, and stroke [2]. In ∼30% of cases, seizures are not controlled by current therapeutic options. Epileptogenesis is likely a continuous process developing over weeks, months, or even years beyond the initial insult [4,5,6]. Treatments for epilepsy may focus on preventing or controlling seizures after epilepsy is established, or ideally, on interrupting the damaging processes during epileptogenesis and preventing onset of spontaneous seizures all together. Understanding of the molecular processes occurring during epileptogenesis, and discriminating the deleterious from the compensatory, will help in developing novel therapeutics
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