Young epilepsy community members presented late-breaking research on Dravet syndrome, hippocampal neuron activity during seizure, and more at AES 2015.
One of the Investigators’ Workshops at AES 2015 focused on hot topics and late-breaking research from 4 young investigators in the epilepsy community. According to moderator Michael Wong, MD, the goal of this workshop was to “feature and promote young investigators in epilepsy research.”
The first investigator, Maneesh Kumar, MD, PhD, of the University of Colorado, presented his research on metabolism in the zebrafish model of Dravet syndrome, a genetic epilepsy characterized by an early, febrile (typically) seizure that progresses into severe, recurring seizures. SCN1A-mutant zebrafish were used because they replicate the phenotype of Dravet syndrome.
The goal was to determine if there were any metabolic defects in Dravet syndrome and, if so, what could be causing them. Kumar first measured baseline glycolysis rates in SCN1A-mutant and wild type zebrafish, which he found to be lower in the mutants. He then treated both types with 4-aminopyridine (4AP), a potassium channel blocker. In the mutant fish he found a delayed, exaggerated response to the 4AP in glycolysis rate.
After testing to eliminate other explanations, Kumar concluded that glycolysis is the difference between the mutants and wild type. He purported that the mutation causing Dravet syndrome changes glycolytic genes, which then affect glycolysis and, in turn, metabolism.
Research presented by investigator Hongyu Sun, MD, PhD, of the University of Pennsylvania, aimed to determine if hippocampal neurons behave differently during seizures. Sun hypothesized that only a selective group of neurons are activated during seizures.
Using the transgenic mouse model, with a c-fos gene promoter, and Green Fluorescent Protein labeling, Sun found that pentylenetetrazol-induced seizures selectively activate a sub-group of neurons in the hippocampus. Further, these activated neurons show increased AMPA-receptor function in post-synaptic membrane.
Sun also determined that functional changes occur only in activated neurons and that the pre-seizure baseline features of the cell may predict susceptibility to a seizure.
With the goal of identifying targets that may be antiepileptogenic, Lauren Andresen, a graduate student at Tufts University, investigated methods of preventing the formation of hyper-excitable networks following injury.
Andresen hypothesized that, targeting thrombospondin increase in Î±2Î´-1, a calcium channel subunit, following freeze lesion injury may decrease maladaptive synaptogenesis and the formation of hyper-excitable networks.
She demonstrated that acute treatment with gabapentin, an antagonist for Î±2Î´-1, prevented synaptogenesis, and the gabapentin itself proved to be neuroprotective.
Further, Andresen explained, a genetic knockout also protected against synaptogenesis, decreasing the formation of a hyper-excitable network, though to a lesser extent than gabapentin.
Shennan Aibel Weiss, MD, PhD, of UCLA, presented his research on the mechanisms that drive seizure stage changes.
He found that the transition from the interictal stage to the preictal stage is not fully known. The transition from preictal to seizure onset “may involve pathological interconnected neuron clusters that coalesce and grow, reaching a critical mass, causing seizure promulgation.” Micro-seizures may facilitate the transition from onset to seizure spread. Finally, the transition between spread and clonic bursting may involve an inhibitory rebound phenomenon.
The AES 2015 Annual Meeting was held December 4-8 in Philadelphia.
Session: Investigators’ Workshop: Hot topics and late-breaking research from young investigators in the epilepsy community. Dec. 6, 2015.