Bi-directional activity driven modification of central synapses is widely believed to be integral to the mechanisms of learning and memory. The hippocampus has been the focus of memory related research, as this cortical structure is clearly essential in the formation and encoding of memories. In particular, a great deal of interest has focused on the mechanisms of hippocampal long-term potential (LTP). Determination of the cellular and molecular mechanisms involved in this form of plasticity are of fundamental importance to better understand the pathological processes involved in the disruption of memory formation and retrieval common in many neurodegenerative illnesses and post- ischemic dementias. It is thought that these CA3 region of the hippocampus functions as a recurrent network that is ideal for the formation of discrete memories. The mechanisms of LTP of one of the major excitatory inputs to principal neurons of the CA3 region, the mossy fibers, are therefore an important research objective in determining hippocampal function. Although a number of features of mossy fiber LTP have been established, some aspects of transmission at this synapse remain controversial. In this study we will address this important, outstanding, mechanistic question. Specifically,, we will test the hypothesis that induction of mossy fiber LTP involves retrograde signaling from the post-synaptic cell to the pre-synaptic nerve terminal. We will test three mechanistic aspects of this hypothesis. First, in order to elucidate the post-synaptic mediators of retrograde signaling, we will disrupt protein-protein interactions in the post-synaptic neuron to determine which post-synaptic factors influence mossy fiber plasticity. Secondly, we will test whether post-synaptic kinase activity is involved in the induction of mossy fiber LTP. Finally, we will investigate which molecules mediate trans-synaptic retrograde signaling at mossy fiber synapses. A complete understanding of the cellular and molecular mechanisms of hippocampal LTP will provide insight into approaches to treat memory related symptoms of neurological disorders.
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