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| Introduction |
| • D'Ambrosio Main |
Epilepsy and Traumatic Brain InjuryBackground: Over 50,000 deaths in the U.S. each year are directly attributable to head injury. Moreover, every year there are over 50,000 survivors of severe head injury with significant neurological sequelae. Even minor head injury (~200,000 persons/year) has a major impact on functional performance after injury, sometimes lasting months or longer. Post-traumatic seizures, disorders of higher cognitive function, including intellectual and memory impairment, emotional lability, decreased concentration, and migraine commonly result from mild traumatic brain injury (TBI). Significant disorders of higher cognitive function may occur despite minimal or no focal neurologic deficit. Furthermore, the occurrence of debilitating epilepsy, one of the most poorly controlled types of epilepsy, has been well documented chronically following head injury. Consequently, TBI has a significant impact on society because of the short and long term costs involved in the care of these patients. In spite of extensive neuropathological investigations of head injury, the neurobiological basis of post-traumatic pathogenic processes still remain largely unknown. In particular, the specific mechanisms that account for acute brain swelling and chronic posttraumatic epilepsy are poorly understood. Previous work has linked post-traumatic neuronal loss and diffuse axonal injury to the neurological disorders that follow traumatic brain injury. However, normal neuronal function also depends on non neuronal mechanisms such as an accurate regulation of the extracellular ionic concentrations and cellular and extracellular volume, the failure of which may result in edema, altered neuronal excitability, synchronization, and delayed neuronal death. These physiological parameters directly involve the glial cell population.
Research Question:Are reactive glial cells capable of proper brain homeostasis?In addition to the neuronal damage, both traumatic brain injury and epilepsy have a feature in common: reactive glia. Glial reactivity –as defined by the occurrence of active cytological, immunological, morphological or functional response of glial cells to central nervous system insults- is thought to promote the functionally important processes of inflammation and tissue repair. Glial cells are known to participate in glial scar formation (“reactive gliosis”), which occurs after trauma to the central nervous system (CNS), but their role in the pathological sequelae of TBI remains controversial, especially with respect to its beneficial or detrimental influence on the recovery of the CNS. Reactive glial cells regulate the removal of toxic compounds or cellular debris, support neuronal growth, and participate in the immunological response to parenchymal injury. However, the extent of glial reactivity is often out of proportion to neuronal injury, and glia may become reactive in areas that do not show neuronal injury, suggesting that -in certain regions and under certain conditions- glia may be responsible for certain pathological processes. Since it is established that glia contribute to brain microenvironment homeostasis, it has been long suspected that reactive glia –by virtue of changes in their membrane properties- may have improper homeostatic capacity and cause abnormal neuronal excitability and function. Indeed, reactive glia differ from resting glia in a number of cellular properties, including their electrophysiological properties and expression of K+-currents which are involved in extracellular K+ homeostasis and in maintaining proper neuronal excitability. The mission of our laboratory is to characterize the physiology and pathophysiology of neuronal-glial interactions, in particular following traumatic brain injury and epilepsy. The ultimate goal is to improve the acute and chronic outcome of traumatic brain injury and epileptic patients by developing novel therapies that target the glial cell population.
Research Highlights:
 Research Methods:Our laboratory utilizes a wide variety of techniques to study neuronal and glial cell pathophysiology:
Lab Members: - Dana DoyleLinks:
UW Regional Epilepsy Center: UW Graduate Program in Neurobiology & Behavior: UW Undergraduate Research in Neurological Surgery, http://webapps.ued.washington.edu/opportunities/Opportunities.aspx?post_ID=210 Center on Human Development and Disability (CHDD)
at the University of Washington: Selected Bibliography:1. D'Ambrosio R, A possible causative role for blood-brain barrier
failure and reactive 2. D'Ambrosio R, Fender JS, Fairbanks JP, Simon EA, Born DE, Doyle DL, Miller JW. Progression from frontal-parietal to mesial-temporal epilepsy after fluid percussion injury in the rat. Brain. 2005, 128(Pt 1):174-88. Epub 2004 Nov 24. 3. D'ambrosio R, Perucca E. Epilepsy after head injury. 4. D'Ambrosio R. The role of glial membrane ion channels in seizures and epileptogenesis. Pharmacol Ther. 2004, 103(2):95-108. 5. D'Ambrosio R, Fairbanks JP, Fender JS, Born DE, Doyle DL, Miller JW. Post-traumatic epilepsy following fluid percussion injury in the rat. Brain. 2003 Nov 7 [Epub ahead of print] 6. D’Ambrosio R, Gordon D.S., and Winn H.R. (2002) Differential roles of KIR channel and Na+/K+-pump in the regulation of extracellular K+ accumulation in rat hippocampus. Journal of Neurophysiology, Vol 87: 87-102. 7. D’Ambrosio R. (2003) Basic science of posttraumatic epilepsy. In: Youman’s Neurological Surgery. 5th edition, pp2449-2460. Elsevier. 8. D’Ambrosio R. The perforated patch technique. In: Neuromethods: Patch Clamp Applications and Protocols. Boulton AA, Baker GB, and Walz W eds.The Humana Press (2002). 9. D’Ambrosio R., Maris D.O., Grady S.M., Winn H.R., and Janigro D. Impaired K+ homeostasis and altered electrophysiological properties of post-traumatic hippocampal glia. Journal of Neuroscience, 19(18): 8152-62. 10. Ngai A.C., Jolley M.A., D’Ambrosio R., Meno J.R. and Winn H.R. (1999) Frequency-dependent changes in cerebral blood flow and evoked potentials during somatosensory stimulation in the rat. Brain Research, 837:221-228. 11. Hochman D.W., D’Ambrosio R., Janigro D., and Schwartzkroin P.A. (1999) Extracellular chloride and the maintenance of spontaneous epileptiform activity in rat hippocampal slices. Journal of Neurophysiology, 81:49-59. 12. D’Ambrosio R., Wenzel J., Schwartzkroin P.A., McKhann G. II and Janigro D. (1998) Functional specialization and topographic segregation of three types of hippocampal astrocytes. Journal of Neuroscience, 18(12):4425-38. 13. D’Ambrosio R., Maris D.O., Grady M.S., Winn H.R. and Janigro D. (1998) Selective loss of Long-Term Potentiation, but not Depression, following fluid percussion injury. Brain Research, Vol. 786 (1-2) pp. 64-79.
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