A promising and widely studied example of vertebrate synaptic plasticity is long-term potentiation (LTP), the persistent synaptic enhancement seen following a brief period of coincident pre- and postsynaptic activity. It has been suggested that the cellular and molecular mechanisms responsible for LTP will elucidate several physiological phenomena including learning, memory, and developmental synapse specificity. An understanding of the mechanisms underlying LTP is important in deciphering the effect of experience on behavior and thus may give insight into the cellular basis of clinical psychiatric disorders. The cellular signalling responsible for generating LTP has been studied extensively. However, there is not yet a consensus in the scientific community regarding the final modification underlying potentiated transmission. In this project I have one specific aim: to determine the nature of synaptic changes responsible for the persistent enhancement of transmission during LTP. Answers to this central question should serve as the cornerstone in understanding the cellular and molecular mechanisms underlying LTP. Due to the recent application of whole-cell voltage-clamp recordings to hippocampal slices, a technique that allows much greater signal resolution, we are in a position to see, at a very basic mechanistic level, the intricate processes responsible for LTP. This powerful technique will be applied to answer two questions: 1) Does quantal size change with LTP? and 2) Is there a change in paired-pulse facilitation with LTP? I will use these two questions to test a specific hypothesis that could reconcile the different views currently in the literature regarding expression of LTP: for low levels of potentiation there is primarily a postsynaptic change; large levels of potentiation are due to presynaptic changes. It is hoped that a detailed knowledge of the changes during LTP will elucidate the sites of synaptic modulation in physiological conditions as well as point to critical mechanisms that may be perturbed in pathological states.
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