The long-term objective of the proposed research is to understand how neura activity modifies synaptic connectivity in the adult, the developing, and t e damaged brain. Associative long-term potentiation/depression provides a useful model for studies of activity-dependent synaptic modification becaus associative activity is believed to be the normal mode of synaptic modification in adult brain. My previous research characterized anatomical correlates of long-term potentiation (LTP) in the entorhinal cortex (EC)-dentate gyrus (DG) system and found that the experimentally modified synapses are just like a subset of the normally occurring Gray type-I synapses. The proposed studies attem t to generalize this discovery of an anatomical marker of physiological function to other brain regions so as to enhance the marker's credibility a d utility. Future studies could then identify functional modification with anatomical methods. Specifically, the proposed studies will use extracellular physiology and quantitative electron microscopy to characterize the ultrastructural correlates of LTP at the distal axospinous EC-CA1 synapses. Other studies will quantitatively describe the normal morphology and organization of the EC-CA1 synapses to strengthen interpretations of any morphological correlat s of LTP which are discovered. LTP at the EC-CA1 synapses is not only interesting in its own right but has an additional importance. The distal spine synapses of CA1 are similar in many respects to the EC-DG synapses an to the reasonable transition between the EC-DG system and the pyramids of cerebral cortex, the eventual focus of experimental interest. Analyses of synaptic modification in cerebral cortex will begin by seeking the same subset of Gray type-I synapses in candidate regions of normal cerebral cortex. If the search is successful, then we will have suggestive evidence for an LTP-like process in cerebral cortex. The anatomical method could then be used to study alterations that occur wi h development, after brain injury, after treatments to cure brain injury, or in response to pathologies induced by excessive neural activity (e.g. epilepsy). The rationale for this view is that related activity-dependent mechanisms and the biochemistry thereof underlie functional and dysfunction l synaptic modification throughout the life span of the organism.