A promising and widely studied example of vertebrate synaptic plasticity is long-term potentiation (LTP), the persistent synaptic enhancement seen following a brief period of coincident pre- and postsynaptic activity. The cellular and molecular mechanisms responsible for LTP are thought to participate in physiological and pathological processes including learning, memory, developmental synapse specificity, pain, neuronal death, and dementia. For many years the locus undergoing changes during LTP (pre- and/or postsynaptic) was debated. Identification of the post-synapse as a site of modification has led to considerable advancement in the field. Evidence accrued over the past ten years indicates that delivery of AMPA-type glutamate receptors to synapses plays a critical role during LTP. However, the mechanisms controlling synaptic incorporation of AMPA receptors are not clear. In particular, the path by which AMPA receptors reach synapses during LTP, lateral diffusion and/or exocytosis, is hotly contested. Since these paths employ such mechanistically distinct processes, knowing each of their roles will shed light on the underlying molecular machinery operating during LTP. We have developed molecular, optical and electrophysiological methods in rodent brain slices to elucidate the mechanisms controlling AMPA receptor synaptic incorporation during LTP and experience-driven plasticity. In this grant period we plan to: 1. Measure optically synaptic incorporation of recombinant AMPA receptors. 2. Determine the role played by AMPA receptor exocytosis in LTP. 3. Determine the role played by AMPA receptor lateral diffusion in LTP. 4. Determine the pattern of synaptic potentiation in single neurons following experience-driven plasticity.

Public Health Relevance

Synapses, the sites of communication between nerve cells, are modified during learning and memory. How this modification takes place, at the molecular level, will help scientists understand the biological basis of learning and memory, as well as what goes wrong during diseases such as Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH049159-24
Application #
8431452
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Asanuma, Chiiko
Project Start
1992-05-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
24
Fiscal Year
2013
Total Cost
$420,095
Indirect Cost
$148,189
Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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