It has always been expected that understanding normal brain function, particularly the cellular bases of learning and memory, would lead to clinically relevant results, but no one dared guess how quickly this relevance would arrive. A hypothesis held by several researchers is that brain pathologies resulting from ischemia and anoxia develop because of excessive neural activity. It is not just activity, however, but activity that activates NMDA receptors. The activation of NMDA receptors requires associative activity of the very type we are studying. That is, the NMDA receptors are not there to kill cells but are there to mediate associative learning. The proposed research continues our NIH- funded research and uses anatomy, physiology, and biophysical modeling to extend our knowledge of long-term associative synaptic modification. The extension goes in two directions: one extension is to another synaptic system; the other extension is to relate long-term associative potentiation to induced brain pathologies. The other synaptic system is formed by entorhinal cortical (EC) afferents on the spiny pyramids of hippocampal CAl. Associative potentiation at these synapses is of interest in its own right but has an additional importance. The CAl pyramids represent a sensible transition which should allow a bridging of knowledge gained from the dentate granule cells to the pyramids of cerebral cortex. That is, the distal spine synapses of CAl are quite similar to the EC-DG synapses we have studied and to the layer-l spine synapses of cerebral cortex. In CAl we will study two types of changes: a homogeneous associative potentiation of the bilateral EC projections to the CAl molecular layer, and a heterogenous interaction in which the EC-CAl synapses generate the permissive event for CA3-CAl synaptic modification. The research will evaluate both the ultrastructural and physiological characteristics of these changes. Biophysical models will examine the implications of the morphological alterations for cellular spatiotemporal integration and the rules of LTP. By correlating the ultrastructural characteristics of LTP with the ultrastructural characteristics of epilepsy and of ischemic/traumatic brain injury, we will examine the relationship between associative modification and the relevant class of brain methodologies. The question is: to what extent is LTP a correlate of these pathologies? Key observations will be any ultrastructural correlates shared by LTP and these pathologies. LTP-like changes may be a transitional state before ischemic cell death while the epileptic state may require LTP.
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