Debilitating memory impairment is the most consequential result of Alzheimer's disease. Pathological changes in selective regions of the hippocampal formation, an area of the CNS important for the acquisition and consolidation of certain types of information into long-term memory (8), are found in Alzheimer's patients (7). Long-term potentiation (LTP) of synaptic transmission is a leading candidate mechanism for memory storage in the CNS and can be expressed at all major excitatory synapses within the hippocampus (1). A general hypothesis is that the hippocampus stores information, through LTP, for later consolidation into long-term memories in other brain areas. We are therefore interested in how the hippocampus processes and stores information. The mossy fibers are a major excitatory afferent pathway into the CA3 region of the hippocampus. They are axons of dentate granule neurons and synapse onto CA3 pyramidal neurons. Synaptic transmission at the mossy fibers is through excitatory amino acids, but they also release a number of opioid peptides (6). Mossy fiber LT? (MF-LT?) has a number of unique properties compared to most other excitatory synapses of the hippocampus. Most notably, it is not dependent upon N-methyl-D-aspartate receptors (2). MF-LT? is also dependent upon opioid receptor activation (5). Furthermore, there appear to be two forms of MF-LT? (9). One form is triggered by solely a presynaptic mechanism (11). The other form is dependent upon postsynaptic depolarization and an increase in postsynaptic calcium (4, 10)and is therefore Hebbian; it requires conjunctive presynaptic and-postsynaptic activation (3). This is important because neural networks connected by Hebbian synapses have the potential for associative information storage. Recent work in our laboratory suggests that there are at least two potential sources of calcium available to trigger this form of MF-LT?, including voltage-gated calcium entry and the release of calcium from intracellular s tores. I We propose to study the biophysical and pharmacological mechanisms involved in triggering mossy fiber LTP. We will use the in vitro hippocampal slice preparation and a combination of extracellular, whole-cell, and fluorescence imaging methods for these studies. The results of these experiments will be important for our understanding of the mechanisms underlying associative information storage in the hippocampal formation.
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