The Epilepsy Research Laboratories have a research focus directed towards establishing a better understanding of the basic mechanisms of epilepsy and epileptogenesis. This is centered on the overarching idea that only by better understanding the fundamental, underlying determinants driving seizure disorders can we learn to better treat, and someday cure, these devastating neurologic conditions.

Epilepsy is a condition defined by the occurrence of recurrent, spontaneous seizures, and seizures are hyper-synchronous discharges of populations of neurons. Therefore, epilepsy is fundamentally a disorder of neuronal circuits. Only through study of the dynamics of these complex brain networks both in health and in disease can we hope to further our knowledge of mechanisms disrupting the behavior of specific circuits within the brain.

Neuronal circuit dynamics are an emergent function of the behavior of thousands or tens of thousands of diverse, interconnected cells, each with its own intrinsic excitability, afferent output, and efferent input. These neurons influence each other’s activity in a dynamic, interactive, and spatially and temporally complex manner. Astrocytes also contribute significantly to emergent neuronal circuit dynamics. Recordings from single neurons, although informative, are difficult to extrapolate to circuit level responses. Our laboratories have focused our energies on dynamic characterization of the function of neuronal circuits, integrating a combination of techniques to fully interrogate all aspects of brain network behavior, both in control and in models of epilepsy.

Technical approaches utilized in the laboratory include 1) functional epifluorescence imaging of transmembrane voltage changes in populations of neurons, 2) multiphoton and confocal imaging of intracellular calcium dynamics both in individual neurons and large populations of neurons, 3) fluorescence lifetime and multiphoton imaging of transmembrane chloride dynamics both in individual neurons and in populations of neurons, 4) multielectrode array recording of neuronal activation within hippocampal microcircuits, 5) transgenic labeling and gene targeting in specified subpopulations of neurons, 6) optogenetic activation and silencing of specified populations of neurons and 6) patch clamp and extracellular recording techniques.

Integrating these diverse techniques enables us to cover sufficient parameter space to ensure that we capture all aspects of circuit dynamics with sufficient temporal resolution to resolve both action potentials and synaptic responses in neurons, and with sufficient spatial resolution to record responses in large populations of individually identified neurons and neuronal subcompartments, including cell somata and dendrites. Comparing these measures of neuronal circuit behavior between control, models of epilepsy, and surgical specimen resected from patients with intractable epilepsy affords us an unprecedented depth of understanding both of normal and pathological function of brain networks, critical in developing novel therapies for epilepsy treatment, prevention, and ultimately, cure.

Douglas A. Coulter, PhD