Drug discovery in epilepsy has historically been biased towards transmembrane channels and receptors. Ibhazehiebo et al. describe a novel, metabolism-based drug discovery platform that assays for bioenergetic changes in zebrafish models, and demonstrate that histone deacetylases 1 and 3 decrease mitochondrial hyperexcitability and represent a combined target for anti-seizure drug development.

Sudden unexpected death in epilepsy (SUDEP) is a leading cause of premature mortality in patients with epilepsy, and has been linked to multiple risk factors, including gender and early age at seizure onset. Despite the lack of a targeted therapy for SUDEP, it has recently been shown that a high-fat, low carbohydrate ketogenic diet (KD) enhances longevity in the epileptic Kcna1-null (KO) mouse, a validated model of SUDEP. Here, we asked whether the KD-driven prolongation of lifespan in KO mice is dependent on sex and/or age at treatment onset. We found that as KO mice aged, their daily seizure frequency steadily increased, but had early demise by postnatal day (PD) 46.9±0.8. In KO mice started on the KD at PD30, longevity was extended to a mean of PD69.8±1.7, accompanied with improved seizure control. Interestingly, while seizure control on the KD was similar between male and female mice, KD-fed female KO mice survived longer than their male counterparts. Further, epileptic mice initiated on the KD at PD25 had longer lifespans compared to those placed on the KD starting at PD35. Collectively, these data further support the notion that the KD can retard disease progression and sudden death in KO mice, but that this beneficial action is influenced by gender and age at the start of treatment.

Narcolepsy Type 1 (NT1), a sleep disorder with similar prevalence in both sexes, is thought to be due to loss of the hypocretin/orexin (Hcrt) neurons. Several transgenic strains have been created to model this disorder and are increasingly being used for preclinical drug development and basic science studies, yet most studies have solely used male mice. We compared the development of narcoleptic symptomatology in male vs. female orexin-tTA; TetO-DTA mice, a model in which Hcrt neuron degeneration can be initiated by removal of doxycycline (DOX) from the diet. EEG, EMG, subcutaneous temperature, gross motor activity and video recordings were conducted for 24-h at baseline and 1, 2, 4 and 6 weeks after DOX removal. Female DTA mice exhibited cataplexy, the pathognomonic symptom of NT1, by Week 1 in the DOX(-) condition but cataplexy was not consistently present in males until Week 2. By Week 2, both sexes showed an impaired ability to sustain long wake bouts during the active period, the murine equivalent of excessive daytime sleepiness in NT1. Subcutaneous temperature appeared to be regulated at lower levels in both sexes as the Hcrt neurons degenerated. During degeneration, both sexes also exhibited the “Delta State”, characterized by sudden cessation of activity, high delta activity in the EEG, maintenance of muscle tone and posture, and the absence of phasic EMG activity. Since the phenotypes of the two sexes were indistinguishable by Week 6, we conclude that both sexes can be safely combined in future studies to reduce cost and animal use.