The goal of the proposed research is to determine the underlying mechanisms for short-term and long lasting changes in striatal synaptic function created by transient mitochondrial inhibition. My laboratory has demonstrated that aged rats consistently show a loss of facilitating synapses and, remarkably, that low doses of 3-nitropropionic acid (3-NP) (single i.p. injection, 20 mg/kg) caused an enduring change in corticostriatal synaptic function that mimics this synaptic phenotype of aging. To gain insight into the mechanisms underlying this enduring 3-NP-mediated change in synaptic function, we examined rats 24 hours after the injection and found an opposite trend: a dramatic increase in the expression of long-term potentiation (LTP). Experiments outlined in Specific aim 1 will examine the time course of 3-NP induced changes in corticostriatal synaptic function to provide data about the transition from 3-NP induced LTP to long-term depression (LTD), as well as new information about how long the 3-NP induced increase in corticostriatal synaptic depression lasts. Experiments outlined in Specific Aim 2 will investigate the role played by NMDA receptor and dopamine (DA) receptor activation in the 3-NP-mediated enhancement of LTP expression 24 hours after 3-NP exposure. Experiments outlined in Specific Aim 3 will examine the role played by reactive oxygen species (ROS) in mediating 3-NP induced changes in synaptic function. While it is clear ROS are involved in changes associated with mitochondrial dysfunction, the striatum is unique in the potential interaction between ROS and (DA) physiology. Experiments outlined in Specific Aim 4 will examine the role played by DA and its oxidation in the expression of 3-NP induced changes in synaptic function. Parallel analyses of changes in DA biochemistry and in the numbers of DA receptors will be performed to gain greater insight into how changes in DA physiology contribute to 3-NP induced changes in corticostriatal synaptic function. The experiments outlined in Specific Aim 5 will determine if the 3-NP-induced changes in corticostriatal plasticity can generalize to reversible inhibition of complex II by malonate. In total, information gained from these experiments will provide new insight into mechanisms of synaptic change resulting from mitochondrial inhibition as well as a correlative framework for similar mechanisms, which may occur in aging and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG021937-04
Application #
7265101
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Wise, Bradley C
Project Start
2004-08-01
Project End
2010-07-31
Budget Start
2007-08-01
Budget End
2010-07-31
Support Year
4
Fiscal Year
2007
Total Cost
$192,213
Indirect Cost
Name
University of Southern California
Department
Type
Organized Research Units
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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