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

Abstract

Background 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. However, this has not been systematically investigated at the synaptic level, and the underlying molecular mechanisms remain to be elucidated. Methods Kainic 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. Results We 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. Conclusion Our 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.

Agrin-Lrp4 pathway in hippocampal astrocytes restrains development of temporal lobe epilepsy through adenosine signaling

“…Western blotting was performed as described in our previous study [ 52 ]. In brief, brain tissue was homogenized in a RIPA Buffer containing (in mM): 50 Tris–HCl, pH 7.4, 150 NaCl, 2 EDTA, 1 PMSF, 50 sodium fluoride, 1 sodium vanadate, 1 DTT with 1% sodium deoxycholate, 1% SDS and 1% protease inhibitors cocktails.…”

Molecular Mechanisms Underlying the Bioactive Properties of a Ketogenic Diet

“…A variety of studies have reported that KD treatment elevated GABA levels in both human and animal brains, but it remains unclear whether changes in glutamate also occur [50][51][52]. GABAergic but not glutamatergic activity in the hippocampus was found to be enhanced by a KD in preclinical models of both acute and chronic seizures, and those changes were shown to be mediated by Nrg1/ErbB4 signaling [53]. Intriguingly, a long-term (i.e., 3 months) KD modified expression of the potassium chloride cotransporter 2 (KCC2), but not that of Na-K-Cl cotransporter 1 (NKCC1), in the dentate gyrus of rats [54], while 1 month of a KD was not effective at altering the expression of both transporters [55].…”

On the nutritional and therapeutic effects of ketone body d-β-hydroxybutyrate

“…It was recently demonstrated that d-3HB elicited its anti-epileptic effect through activation of K ATP channels and GABA B signaling, which led to reduced neuronal firing (Li et al 2017). Recent studies have revealed novel signaling pathways by which d-3HB may be involved (Wang et al 2021), as well as its potential for treating other forms of epilepsy (Brunner et al 2021).…”