Search

Glia-Neuron Interactions Underlie State Transitions to Generalized Seizures Diaz Verdugo C, Myren-Svelstad S, Aydin E, et al. Nat Commun. 2019;10:3830. doi:10.1038/s41467-019-11739-z. Brain activity and connectivity alter drastically during epileptic seizures. The brain networks shift from a balanced resting state to a hyperactive and hypersynchronous state. It is, however, less clear which mechanisms underlie the state transitions. By studying neural and glial activity in zebrafish models of epileptic seizures, we observe striking differences between these networks. During the preictal period, neurons display a small increase in synchronous activity only locally, while the gap-junction-coupled glial network was highly active and strongly synchronized across large distances. The transition from a preictal state to a generalized seizure leads to an abrupt increase in neural activity and connectivity, which is accompanied by a strong alteration in glia-neuron interactions and a massive increase in extracellular glutamate. Optogenetic activation of glia excites nearby neurons through the action of glutamate and gap junctions, emphasizing a potential role for glia–glia and glia–neuron connections in the generation of epileptic seizures. [ABSTRACT FROM AUTHOR]

The epilepsies are a complex group of disorders that can be caused by a myriad of genetic and acquired factors. As such, identifying interventions that will prevent development of epilepsy, as well as cure the disorder once established, will require a multifaceted approach. Here we discuss the progress in scientific discovery propelling us towards this goal, including identification of genetic risk factors and big data approaches that integrate clinical and molecular 'omics' datasets to identify common pathophysiological signatures and biomarkers. We discuss the many animal and cellular models of epilepsy, what they have taught us about pathophysiology, and the cutting edge cellular, optogenetic, chemogenetic and anti-seizure drug screening approaches that are being used to find new cures in these models. Finally, we reflect on the work that still needs to be done towards identify at-risk individuals early, targeting and stopping epileptogenesis, and optimizing promising treatment approaches. Ultimately, developing and implementing cures for epilepsy will require a coordinated and immense effort from clinicians and basic scientists, as well as industry, and should always be guided by the needs of individuals affected by epilepsy and their families. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century – From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'. • Basic research has increased our understanding of epilepsy. • 1/3 of patients still have seizures resistant to current therapies. • We are making significant progress in understanding the biological basis of epilepsy. • Exciting new technologies and insights put new therapies in our sights. • Basic research is essential for the development of effective treatments over the long term. [ABSTRACT FROM AUTHOR]

The 2014 NINDS Benchmarks for Epilepsy Research included area I: Understand the causes of the epilepsies and epilepsy-related neurologic, psychiatric, and somatic conditions. In preparation for the 2020 Curing Epilepsies Conference, where the Benchmarks will be revised, this review will cover scientific progress toward that Benchmark, with emphasize on studies since 2016. [ABSTRACT FROM AUTHOR]

Status epilepticus (SE) is a neurological emergency characterized by continuous seizure activity lasting longer than 5 min, often with no recovery between seizures (Trinka et al., 2015). SE is refractory to benzodiazepine and second-line treatments in about 30% cases. Novel treatment approaches are urgently needed as refractory SE is associated with mortality rates of up to 70%. Robust adenosinergic anticonvulsant effects have been known for decades, but translation into seizure treatments was hampered by cardiovascular side effects. However, the selective adenosine A1 receptor agonist SDZ WAG 994 (WAG) displays diminished cardiovascular side effects compared to classic A1R agonists and was safely administered systemically in human clinical trials. Here, we investigate the anticonvulsant efficacy of WAG in vitro and in vivo. WAG robustly inhibited high-K+-induced continuous epileptiform activity in rat hippocampal slices (IC 50 = 52.5 nM). Importantly, WAG acutely suppressed SE in vivo induced by kainic acid (20 mg/kg i.p.) in mice. After SE was established, mice received three i.p. injections of WAG or diazepam (DIA, 5 mg/kg). Interestingly, DIA did not attenuate SE while the majority of WAG-treated mice (1 mg/kg) were seizure-free after three injections. Anticonvulsant effects were retained when a lower dose of WAG (0.3 mg/kg) was used. Importantly, all WAG-treated mice survived kainic acid induced SE. In summary, we report for the first time that an A1R agonist with an acceptable human side-effect profile can acutely suppress established SE in vivo. Our results suggest that WAG stops or vastly attenuates SE while DIA fails to mitigate SE in this model. • A1R agonist SDZ WAG 994 suppresses kainate status epilepticus (SE) in vivo in mice. • 0.3 and 1 mg/kg WAG, but not 5 mg/kg Diazepam, attenuate or stop established SE. • Low nanomolar concentrations of WAG vastly reduce epileptiform activity in vitro. • WAG IC 50 against high-K+ epileptiform activity in rat hippocampal slices: 52.5 nM. [ABSTRACT FROM AUTHOR]