? ? Traumatic brain injury often results in epilepsy that is poorly controlled by antiepileptic drugs. Although there is evidence that axonal sprouting, enhanced excitatory synaptic connectivity and reduced inhibitory synaptic transmission are associated with posttraumatic epileptogenesis; further information on how these changes occur and contribute to epileptogenesis is incomplete. This information is crucial in providing a rational basis for the development of new therapies aimed to disrupt posttraumatic epileptogenesis. In the proposed study, I will use the partial cortical isolation (""""""""undercut"""""""") model and a novel organotypic slice culture model of posttraumatic epileptogenesis to investigate alterations in excitatory and inhibitory synaptic connectivity. Three specific questions will be addressed: (1) Is there an increase in excitatory synaptic coupling between layer V pyramidal neurons after a chronic partial cortical isolation? (2). Is there a decrease in inhibitory synaptic input from fast-spiking interneurons to layer V pyramidal cells after such a lesion? (3) Does axonal sprouting play a critical role in posttraumatic epileptogenesis? I will use a combination of single and paired whole cell recording, laser scanning photostimulation (LSP), transgenic mice, organotypic brain slice culture and time-lapse confocal microscopy techniques. An LSP-guided dual whole cell recording technique will be developed to improve efficiency of paired recordings. The results of these experiments will identify and characterize alterations in excitatory and inhibitory synaptic transmission in the epileptogenic neocortex, document morphological dynamics during axonal sprouting following injury, and establish a novel in vitro model of posttraumatic epileptogenesis. Results will contribute to a further understanding of normal synaptic circuitry and pathological changes involved in posttraumatic epilepsy and provide insights for development of novel therapies for preventing posttraumatic epileptogenesis. The investigations during the mentored phase will occur in a fully equipped and well-supported research laboratory of the Department of Neurology at the Stanford University. The sponsor has trained numerous students and fellows, many of whom are now prominent in the field of neuroscience. The training activities support by this award will greatly benefit the candidate's transition to become an independent investigator in the field of epilepsy research. A faculty committee will provide advice and evaluations of progress to the grantee during the award period. ? ? ?
