Mechanisms of synaptic LTP

Cold Spring Harbor Laboratory, Cold Spg Hbr NY

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Abstract

A promising and widely studied example of vertebrate synaptic plasticity is long-term[unreadable] potentiation (LTP), the persistent synaptic enhancement seen following a brief period of[unreadable] coincident pre- and postsynaptic activity. The cellular and molecular mechanisms[unreadable] responsible for LTP will likely elucidate physiological and pathological phenomena[unreadable] including learning, memory, developmental synapse specificity, neuronal death, and[unreadable] dementia. The cellular signaling responsible for generating LTP has been studied[unreadable] extensively. There is now compelling evidence that there is delivery of AMPA-type[unreadable] glutamate receptors to synapses during LTP. Here we will examine the cellular and[unreadable] molecular mechanisms of AMPA receptor delivery to synapses. We will characterize[unreadable] constitutive and regulated synaptic delivery. A specific model is proposed and tested. A[unreadable] regulated pathway effects transient delivery of receptors. The increased levels of[unreadable] receptors at synapses are maintained by constitutive one-for-one exchange between[unreadable] intracellular and synaptic pools. These issues will be examined with several[unreadable] complementing methodologies including electrophysiology, two-photon imaging of GFP-tagged[unreadable] receptors, molecular biology and transgenic technology. These studies will use rodent[unreadable] hippocampal slices (acute and organotypic). In this grant period we plan to: 1. measure[unreadable] delivery of recombinant AMPA receptors to synapses 2. determine which AMPA receptor[unreadable] subunits and domains control constitutive and regulated synaptic delivery 3. generate[unreadable] transgenic mice with dominant negative AMPA-receptor mutations that perturb regulated or[unreadable] constitutive delivery.