AGE-RELATED LOSS OF FACILITATING CORTICOSTRIATAL SYNAPSES MAY BE RELATED TO AN INTERACTION BETWEEN STRIATAL DOPAMINE AND REACTIVE OXYGEN SPECIES
G. Akopain 1, C. Crawford 2, L. Yang L. 3, M.F. Beal MF3, Walsh J.P.1*
1Andrus Gerontology Center & USC Program in Neuroscience, University of Southern California, Los Angeles, CA 90089-0191. 2Department of Psychology, California State University at San Bernardino, San Bernardino, CA 92407. 3Department of Neurology, Cornell University Medical College, New York, NY 10021
Motor difficulties occur earlier in life than cognitive problems and are insensitive to methods of intervention which reduce age-related cognitive deficits. The basal ganglia play an important role in regulating movements and change within this collection of brain nuclei contributes to age-related motor disturbances. Studies showing limited age-related cell loss in the striatum indicate changes in synaptic circuitry and not cell loss may explain age-associated movement problems. We have shown age-related decreases in facilitating corticostriatal synapses spans across all forms of use-dependent plasticity investigated (paired-pulse, short- and long-term). Age-related changes in corticostriatal synaptic plasticity are insensitive to block of L-type Ca2+ channels and thus can not be explained by the age-related increase in L-type Ca2+ expression shown to alter synaptic plasticity in the hippocampus.
The striatum is particularly vulnerable to experimentally induced increases in reactive oxygen species (ROS), partly through the formation of highly reactive dopamine (DA) quinones. We theorized less intense exposure to ROS, which does not cause cell death, may contribute to the loss of facilitating corticostriatal synapses seen in aged animals. To test this hypothesis we delivered a single i.p. injection of 3-nitropropionic acid (3-NP) to young Fischer 344 rats and examined their synaptic plasticity. 24 hours after the 3-NP injection we observed changes in corticostriatal synaptic plasticity which were consistent with a reduction in dopamine modulation. HPLC measurements confirmed striatal slices had experienced a dramatic reduction in DA content and an associated increase in DOPAC 24 hours after the 3-NP injection. However, this acute change in synaptic plasticity was opposite to the naturally occurring change in synaptic plasticity observed in aged animals. We next inve!
stigated the lasting consequences of 3-NP exposure by studying animals one month after the 3-NP injection. We found all features of corticostriatal synaptic aging were mimicked in young animals exposed to 3-NP one month earlier. The synaptic changes included a loss of paired-pulse, short-term and long-term potentiation as well as reduced sensitivity to block of D2 dopamine receptors. This latter change (D2 insensitivity) serves as a functional readout of the well documented age-related decline in striatal D2 dopamine receptor expression. Striatal dopamine content (HPLC) returned to normal in rats examined one month after the 3-NP injection, indicating the permanent change in corticostriatal synaptic plasticity was not related to a change in dopamine content. These data indicate acute block of mitochondrial respiration by 3-NP can cause lasting changes in corticostriatal synaptic function which mimic the aging process. This study also indicates the 3-NP induced change in synaptic plasticity may be due to a toxic cascade initiated by ROS interaction with striatal dopamine.
Key words:
ROS, dopamine, aging, 3-NP, striatum, plasticity
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