Prevention of Postraumatic Neocortical Epileptogenesis


Principal Investigator: Kevin D Graber
Abstract: Epilepsy following head trauma often appears after a quiescent period of months or years. In the rat "undercut" model of posttraumatic epileptogenesis, tetrodotoxin (TTX) treatment will prevent epileptogenesis, allowing comparison of epileptogenic and non-epileptogenic injured neocortex. More information about changes in cortical circuitry following epileptogenic injuries is fundamental to progress in developing prophylaxis or new treatments suitable for humans. This project focuses on the function and critical role of inhibition and excitatory coupling in the undercut model. Patch clamp techniques will be used to evaluate miniature, spontaneous and evoked inhibitory currents in pyramidal neurons in epileptogenic and non-epileptogenic injured neocortical slices from rats several weeks following surgical cortical isolations. Excitatory synaptic coupling will be investigated using laser uncaging of caged glutamate, to map topographic fields of inputs. Also, expression of numerous mRNAs in these tissues will be examined using Affymetrix Rat Genome microarrays, to better understand the TTX effect and identify new potential targets for preventing and curing epilepsy. Candidate antiepileptic genes will be further characterized with Q-PCR experiments, and corresponding proteins investigated with immunocytochemistry and western blot. Investigations will occur in a fully equipped and well-supported epilepsy research laboratory of the Department of Neurology and Neurological Sciences at Stanford University. The sponsor has trained numerous students and fellows, many of whom are now prominent in the field of neurophysiology and epilepsy. A new co-mentor within the department, also with extensive resources and experience, will advise molecular and genomic studies. An outstanding neuroscience faculty, a critical mass of post-doctoral fellows in the Stanford Epilepsy Training Program, numerous seminars and courses are available to enrich and supplement the laboratory training. Extension of the award period will allow acquisition of additional techniques in molecular biology and research experience and allow needed time to complete and publish projects, dramatically improving the likelihood of success in an academic career as a clinician/scientist and independent investigator in epilepsy.
Funding Period: 2000-07-01 - 2007-03-31
more information: NIH RePORT