SYNAPTIC PLASTICITY AFTER TRAUMATIC BRAIN INJURY

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The objective of this project is to investigate synaptic modification and damage after traumatic brain injury (TBI) and to propose its possible role in the behavioral and cognitive changes, and neuronal death seen in this condition. We, as well as many others, have found that LTP is impaired, and behavioral deficits developed after TBI in rats. In spite of the large body of evidence obtained from neurophysiological and behavioral studies linking changes of neurotransmission to the sequelae of TBI, few studies deal with the possible morphological, molecular and biochemical modifications of synapses per se underlying the functional changes and neuronal loss. This may be, in part, because conventional electron microscopic methods cannot easily detect morphological modification of synapses after injury, while biochemical and molecular biological methods for such studies are often complicated by the contamination of other subcellular components in the analyzed samples. We have recently established a series of techniques to study changes after brain insults, and found dramatic ultrastructural, molecular and biochemical changes of synapses after brain ischemia. The focus of the present application is to study ultrastructural and molecular reorganization and biochemical modification of synapses after TBI, and to test the hypothesis that the reorganization and modification of damage of synapses may contribute to the functional changes and the slow type of neuronal loss seen after TBI. The Specific Aims are: 1). To study ultrastructural modification of synapses after TBI by quantitative electron microscopy (EM) and EM tomography. 2). To investigate molecular reorganization of synapses after TBI first by purification of synapses, then performing proteomics in conjunction with microsequencing using purified synapses. 3). Study glutamate receptor expression, turnover and interaction with protein kinases after TBI. 4). To study LTP and LTD after TBI and to correlate the LTP and LTD changes with the possible morphological, molecular and biochemical synaptic changes after TBI. Synaptic junction is a very dynamic and plastic process that is regulated via morphological, molecular and post-translational biochemical modification of synapses However, severe insults may cause damage of synapses. Such modification and damage may represent fundamental processes in synaptic plasticity and damage after injury. Knowing these modifications and damage are keys to developing therapeutic interventions. In this application, we propose studies designed to investigate the modification and damage of synapses after TBI.