Neuregulin 1/ErbB4 signaling contributes to the anti-epileptic effects of the ketogenic diet

Jin Wang,Jia-Hui Wu,Aiguo Xuan,Shan Yao,Ying Wang,Min-Dong Xu,Hui-Bin Li,Feng Gao,Xiang-Dong Sun,Cui-Hong Wu,Guo-Bin Huang,Chang-Qin Zhao,Wei Jie,Yun-Long Zhang,Jie Huang,Zi-Hao Deng,Renjie Jiao,Yuan-Quan Li

doi:10.1186/s13578-021-00536-1

Abstract

BackgroundThe ketogenic diet (KD) has been recognized as a potentially effective therapy to treat neuropsychiatric diseases, including epilepsy. Previous studies have indicated that KD treatment elevates γ-Amino butyric acid (GABA) levels in both human and murine brains, which presumably contributes to the KD’s anti-seizure effects. However, this has not been systematically investigated at the synaptic level, and the underlying molecular mechanisms remain to be elucidated.MethodsKainic acid (KA)-induced acute and chronic seizure models were utilized to examine the effects of KD treatment on seizure threshold and epileptogenesis. Synaptic activities in the hippocampus were recorded with the technique of electrophysiology. The effects of the KD on Neuregulin 1 (Nrg1) expression were assessed via RNA sequencing, real-time PCR and Western blotting. The obligatory role of Nrg1 in KD’s effects on seizures was evaluated through disruption of Nrg1 signaling in mice by genetically deleting its receptor-ErbB4.ResultsWe found that KD treatment suppressed seizures in both acute and chronic seizure models and enhanced presynaptic GABA release probability in the hippocampus. By screening molecular targets linked to GABAergic activity with transcriptome analysis, we identified that KD treatment dramatically increased the Nrg1 gene expression in the hippocampus. Disruption of Nrg1 signaling by genetically deleting its receptor-ErbB4 abolished KD’s effects on GABAergic activity and seizures.ConclusionOur findings suggest a critical role of Nrg1/ErbB4 signaling in mediating KD’s effects on GABAergic activity and seizures, shedding light on developing new therapeutic interventions to seizure control.

Highlights

The ketogenic diet (KD) has been recognized as a potentially effective therapy to treat neuropsychiatric diseases, including epilepsy
The ketogenic diet exhibits protective effects in both acute and chronic seizure models To examine the effects of the ketogenic diet (KD) on seizure, we first fed adult male mice with the KD or composition-matched control diet (CD) for 3 weeks (Fig. 1a and b)
These results indicate that KD treatment successfully induces a state of increased ketone bodies in mice

Summary

Introduction

The ketogenic diet (KD) has been recognized as a potentially effective therapy to treat neuropsychiatric diseases, including epilepsy. Previous studies have indicated that KD treatment elevates γ-Amino butyric acid (GABA) levels in both human and murine brains, which presumably contributes to the KD’s anti-seizure effects. This has not been systematically investigated at the synaptic level, and the underlying molecular mechanisms remain to be elucidated. Being a part of bioenergetics medicine therapies, the KD is frequently utilized either alone or in combination with other anti-seizure drugs to treat refractory epilepsy [2]. The exact molecular mechanisms through which the KD induces beneficial effects on controlling seizures remain obscure

Methods

Results

Conclusion