Abstract
BackgroundThe ketogenic diet (KD)has been considered an effective treatment for epilepsy, whereas its underlying mechanisms remain obscure. We have previously reported that the KD feeding increased Neuregulin 1 (NRG1) expression in the hippocampus; disruption of NRG1 signaling by genetically deleting its receptor-ErbB4 abolished KD’s effects on inhibitory synaptic activity and seizures. However, it is still unclear about the mechanisms underlying the effect of KD on NRG1 expression and whether the effects of KD require ErbB4 kinase activity.MethodsThe effects of the KD on NRG1 expression were assessed via western blotting and real-time PCR. Acetylation level at the Nrg1 promoter locus was examined using the chromatin immunoprecipitation technique. Kainic acid (KA)-induced acute seizure model was utilized to examine the effects of KD and histone deacetylase inhibitor-TSA on seizures. Synaptic activities in the hippocampus were recorded with the technique of electrophysiology. The obligatory role of ErbB4 kinase activity in KD’s effects on seizures and inhibitory synaptic activity was evaluated by using ErbB kinase antagonist and transgenic mouse-T796G.ResultsWe report that KD specifically increases Type I NRG1 expression in the hippocampus. Using the chromatin immunoprecipitation technique, we observe increased acetylated-histone occupancy at the Nrg1 promoter locus of KD-fed mice. Treatment of TSA dramatically elevates NRG1 expression and diminishes the difference between the effects of the control diet (CD) and KD. These data indicate that KD increases NRG1 expression via up-regulating histone acetylation. Moreover, both pharmacological and genetic inhibitions of ErbB4 kinase activity significantly block the KD’s effects on inhibitory synaptic activity and seizure, suggesting an essential role of ErbB4 kinase activity.ConclusionThese results strengthen our understanding of the role of NRG1/ErbB4 signaling in KD and shed light on novel therapeutic interventions for epilepsy.
Highlights
The ketogenic diet (KD)has been considered an effective treatment for epilepsy, whereas its underly‐ ing mechanisms remain obscure
Treatment of TSA, a broad-spectrum histone deacetylase (HDAC) inhibitor, dramatically elevates Neuregulin 1 (NRG1) expression in the hippocampus and diminishes the difference between the control diet (CD) and KD groups, indicating that KD increases NRG1 expression via up-regulating histone acetylation. Both pharmacological and genetic inhibitions of ErbB4 kinase activity significantly block the KD’s effects on inhibitory synaptic activity and seizure, suggesting an essential role of ErbB4 kinase activity. These results strengthen our understanding of the role of NRG1/ErbB4 signaling in KD
We observed significantly increased occupancy of both acetylated H3 and H4 histones at the Nrg1 promoter locus in KD-fed mice compared with those in CD-fed mice (Fig. 2D and E; Additional file 1: Fig. S2A, B), suggesting a potential effect of histone acetylation on NRG1 expression
Summary
The ketogenic diet (KD)has been considered an effective treatment for epilepsy, whereas its underly‐ ing mechanisms remain obscure. We have previously reported that the KD feeding increased Neuregulin 1 (NRG1) expression in the hippocampus; disruption of NRG1 signaling by genetically deleting its receptor-ErbB4 abolished KD’s effects on inhibitory synaptic activity and seizures. It is still unclear about the mechanisms underlying the effect of KD on NRG1 expression and whether the effects of KD require ErbB4 kinase activity. Approximately one-third of the patients exhibit resistance to drug treatments [2], which expresses the urge to identify novel molecular targets for epilepsy to develop highly potent therapeutic strategies. Understanding the critical cellular and molecular mechanisms underlying the therapeutic effects of the KD will provide insights into mechanisms of epilepsy and facilitate developing effective pharmacological strategies
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