Molecular Mechanisms of plasticity in the hippocampus

Activity driven modification of excitatory synapses underlies the refinement of synaptic connections during development and maintenance and adaptation of synapses in mature animals.  Long-term changes in synaptic efficacy are widely accepted to be integral to the formation and consolidation of memories. Due to the complexity and heterogeneity of the processes involved, 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.

Much of our research is concentrated upon the CA3 region of the hippocampus. Synaptic transmission in this region has been less well described than other regions of the hippocampus. However the CA3 presents an interesting and unique functional segment of the hippocampus. This region is critically involved in associative memory processing, and disruption of plasticity mechanisms at excitatory synapses in principal neurons in the CA3 disrupts highly specific forms of associative learning. Additionally, the high interconnectivity of CA3 pyramidal neurons forms a recurrent network in the CA3 which is readily excitable, accounting for the generation of synchronous activity such as that occurring during temporal lobe seizures.

The mossy fiber synapse in the hippocampus is formed between the axons of granule cells in the dentate gyrus and the proximal dendrites of CA3 pyramidal neurons. Induction of LTP at these synapses does not require the activation of postsynaptic NMDA receptors and is expressed as a presynaptic increase in glutamate release probability. In an attempt to fully characterize plasticity at this synapse we have recently demonstrated that one form of mossy fiber LTP requires postsynaptic mechanisms.  Our studies have revealed a novel and integral role for Eph receptor tyrosine kinases and ephrins in mediating mossy fiber LTP. Eph receptors/ephrins have been primarily defined as mediators of axon guidance and cell migration during development. However, these receptors show prominent expression after development and are localized to excitatory synapses. EphB receptors are transmembrane signaling molecules which interact with their membrane bound ligands, the ephrins, to effect intercellular signaling.  Disruption of Eph receptor - ephrin signaling significantly impairs mossy fiber LTP.  Our studies demonstrate a novel trans-synaptic signaling mechanism involved in the persistent increase in glutamate release associated with mossy fiber LTP.  On-going studies are focused on defining the exact mechanism by which these molecules exert their actions.

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Ephrin B3 expression in
the mouse brain.