Astrocyte Dysfunction Contributes to the Development of TBI-Induced Epilepsy

For years, scientists have focused on neuronal damage as the cause of neurological disorders, such as epilepsy. A growing body of evidence shows that impaired astrocyte function happens before seizures manifest.

Traumatic brain injury (TBI) is a primary cause of epilepsy, which is characterized by scar formation that seals off injured areas from healthy brain tissue. These scars are formed by astrocytes. Scars inhibit normal function and have been associated with seizure genesis.

Researchers modeled TBI in mice, using a weight drop injury paradigm, in order to determine whether astrocyte scar formation is involved in TBI-induced epilepsy. While animals developed epilepsy, no scars formed, but astrocytes behaved atypically, with decreased protein expression and decoupling with brain vessels. There were also more atypical astrocytes in epileptic animals. These data support the hypothesis that altered astrocyte function contributes to the development of TBI-induced epilepsy.

Epilepsy – Beyond the Local Network

While human research has emphasized the large scale network disruptions in the epilepsies and their comorbidities, basic science has typically focused on local networks. One of the most important large scale networks in epilepsy is the major state control system, for sleep-wake and vigilance, that controls cortical excitability and cortical rhythms. While these circuits have been elucidated in increasing detail over the last decade, they are still little explored in epilepsy.

Dr. Pedersen will provide an overview of sleep-wake circuitry and its relevance to epilepsy before describing a similar research program and a novel technology in development for better understanding large scale brain networks in the epilepsies and their comorbidities.

Epilepsy and Drug Discovery in Larval Zebrafish

Talk Summary: Zebrafish (Danio rerio) have emerged as a promising and valuable model organism. The increasing popularity of this small vertebrate is evident from the growing numbers of publications and new discoveries associated with the use of zebrafish for studying development, brain function, human disease, and drug screening.

Owing to the development of novel technologies, the range of zebrafish research possibilities is constantly expanding with new imaging, electrophysiological, and gene editing tools enhancing traditional techniques. Despite the widespread success of zebrafish in the neuroscience community, epilepsy research using this organism is more limited. To address this issue, the Baraban Lab began to adapt larval zebrafish for epilepsy related studies almost twenty years ago.

With the rapidly expanding molecular and neuroscience tool box, the lab is now using zebrafish models mimicking human pediatric epilepsies with genetic causes. These genetically modified zebrafish are amenable to rapid drug screening, sophisticated behavioral analysis, long-term electrophysiological monitoring or whole-brain calcium imaging, and hold great potential to advance our understanding and treatment of epilepsy.

In this lecture, Scott Baraban, PhD (University of California San Francisco) will highlight the past and present techniques which have made, and continue to make, zebrafish an attractive model organism in epilepsy research. He will focus on SCN1 mutant zebrafish mimicking a catastrophic form of pediatric epilepsy known as Dravet syndrome, and the lab’s aquarium-to-bedside success screening repurposed drug libraries to identify novel lead compounds for this disorder. Dr. Baraban will also discuss our on-going efforts to use CRISPR/Cas9 genome editing technologies to generate zebrafish mutants for all known human epilepsy genes on the CURE EGI list.

Harnessing Metabolism to Treat Post-Traumatic Epilepsy

Dr Dulla’s lab focuses on the molecular and cellular underpinnings of epilepsy, with a particular emphasis on injury, astrocytes, and glutamate. Using a combination of advanced imaging approaches, genomics, and electrophysiology, the Dulla Lab studies the progression of epilepsy. His current work aims to use metabolic modulation of neuronal excitability to tackle pathologies linked to brain injury.

Dr Dulla will outline his experiments into inhibiting glycolysis after brain injury to prevent the loss of inhibitory GABAergic neurons. He will also describe novel single cell transcriptomics approaches that may shed light on how we might harness metabolism to prevent post-traumatic epilepsy.

Critical Care EEG Monitoring: A Practical Update

Talk Summary

Dr. Hirsch will provide an update in diagnosing and managing seizures, including nonconvulsive ones, and related EEG patterns in critically ill patients. This talk will benefit any member of the health care team involved in inpatient care of patients with altered mental status, including MDs, nurses, PA’s, APRNs, and EEG technologists.

Objectives:

  • To learn which patients are at risk of nonconvulsive seizures and warrant EEG monitoring
  • To learn how to understand EEG reports and which findings require urgent or aggressive treatment
  • To learn how to treat clinical and nonconvulsive seizures in the critically ill most effectively.

Status Epilepticus Research: My Adventures

Talk Summary

The goal of this talk is to highlight importance of novel scientific approaches and team science in epilepsy research. Changing focus from the role GABA -mediated inhibition to AMPA mediated excitatory transmission allowed us to use novel brain mapping techniques and genetic tools to gain novel insights into pathophysiology of status epilepticus.

In an effort to improve patient care, we organized a large, 60 -site clinical trial to investigate treatment of benzodiazepine-refractory status epilepticus, called Established Status Epilepticus Treatment Trial (ESETT). Organization and execution of such a large study required participation of a multidisciplinary team consisting of adult and pediatric ED physicians, adult and pediatric neurologists, trial design experts, biostatisticians , database experts, pharmacists and pharmacologists, and most importantly clinical research coordinators. Team science is critical to improving patient outcomes.