Mechanisms of plasticity at the Mossy Fiber Synapse

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DESCRIPTION (provided by applicant): Activity driven modification of excitatory synapses is an exquisitely powerful process for the refinement of synaptic connections. Long-term potentiation (LTP) of synaptic transmission in the hippocampus is widely accepted to be integral to the formation and consolidation of memories. Due to the complexity and heterogeneity of the molecules underlying LTP, many of the cellular mechanisms are still not fully established. A complete description of these fundamental processes will allow us to understand the pathology of neurological disorders that result in the disruption of memory storage and retrieval. The mossy fiber synapse provides one of the main excitatory inputs to the CA3 region of the hippocampus. The recurrent network of the CA3 is particularly important in the storage and retrieval of associative memories. The mossy fiber synapse is critical to the modulation of this network and therefore is central to hippocampal function. Mossy fiber plasticity demonstrates some very interesting properties. LTP is expressed in the presynaptic terminal of the synapse, however there is still controversy over the site of induction. Recent findings have demonstrated a role for postsynaptic mechanism in the induction of mossy fiber LTP followed by trans-synaptic signaling to the pre-synapse, mediated by Eph receptor-ephrin interactions. In order to further explore the molecules involved in this unique pathway, this study will make use of mutant mice in which the relevant proteins have been genetically ablated or mutated to disrupt their signaling function. In addition, we will explore the exact pre- and postsynaptic mechanisms by which these molecules exert their action. These studies will provide new insight relevant to synaptic transmission and memory processes in the mammalian brain.