Epilepsy Research Laboratory
Department of Neurological Surgery
University of California, Irvine
PROJECTS
INTRODUCTION
Astrocytes, the most abundant glial cell type in the brain, are involved in many important physiologic functions such as neurotransmitter, potassium, and energy metabolism. Accumulating evidence over the past few years suggests that astrocytes may also powerfully modulate brain excitability. Therefore, neuroscientists have begun to investigate the hypothesis that glial cells may contribute to the hyperexcitability of epilepsy. Indeed, pathologic specimens from patients with temporal lobe epilepsy often demonstrate marked reactive gliosis (glial cell scarring), and alterations in distinct astrocyte membrane channels, receptors and transporters have all been associated with various forms of epilepsy.
Our recent research has focused on the study of the astrocyte water channel aquaporin-4. Distinct aquaporin "water channels" have been shown to be important for water transport in many different tissues. In the brain, aquaporin-4 is involved in water and ion metabolism. In recent studies, we have shown powerful alterations in excitability, seizure duration, extracellular space and potassium regulation in aquaporin-4-deficient mice. These results coincide with results demonstrating altered levels of aquaporin-4 in human temporal lobe epilepsy. However, it remains to be determined how the cellular expression and function of aquaporin-4 is altered during the development of epilepsy. Currently, we are examining these and related questions in well-established animal models of epilepsy. The goal of this research is to further understand astrocyte control of water and potassium metabolism in the brain, and how it goes awry in the development of epilepsy. This could directly lead to new concepts and targets for anticonvulsant drug development that may have many fewer side effects than current therapies.
In a parallel project, in collaboration with investigators at the Beckman Laser Institute we have launched a translational imaging project to develop optical tools to measure and detect seizure activity in vivo.
PROJECTS
GLIAL CELLS AND EPILEPSY
- Role of aquaporin-4 glial water channels in the hippocampus
- distribution
- cell type specificity
- regulation by seizures
- Phenotype of aquaporin-4-deficient mice
- behavioral seizure phenotype
- electrophysiology (EEG)
- histopathology (cell death, gliosis)
- Distribution of other astrocyte channels (e.g. Kir4.1 channels) in the hippocampus and alterations in animal models of epilepsy
TRANSLATIONAL IN VIVO IMAGING
- Development of optical tools to measure/detect seizure activity in in vivo models
- Cortical fluorescence recovery after photobleaching (cFRAP)
- Modulated imaging
LABORATORY TECHNIQUES
- Small animal anesthesia and surgery
- Stereotactic neurosurgery in rodents, electrode placement
- Stereotactic injection or infusion
- Osmotic minipump implantation for chronic intracerebral infusion
- In vivo electrophysiology (EEG, K+ microelectrodes)
- Pharmacological and electrical animal models of epilepsy
- EEG recording and analysis
- Histology
- Immunohistochemistry
- Confocal immunofluorescence microscopy
- In situ hybridization
- Western blotting
- PCR
- Fluorescence in vivo imaging
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