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| Title: | AGE-RELATED ALTERATIONS IN THE DYNAMICS OF L-GLUTAMATE REGULATION IN THE STRIATUM OF THE FISCHER 344 RAT |
| Authors: | Nickell, Justin Robert |
| Keywords: | Glutamate
Voltammetry
Aging
GLAST
Freely moving |
| Date Created: | 2006 |
| Publisher: | University of Kentucky |
| Abstract: | L-glutamate is the predominant excitatory amino acid neurotransmitter in
the mammalian central nervous system. Prior aging studies have focused
primarily on dopaminergic circuitry of the striatum, and data obtained studying
glutamate regulation in the striatum have been largely equivocal. These
discrepancies are due in large part to the limitations of microdialysis; while it is
extremely sensitive to minute concentrations of analyte, it is lacking in terms of
the temporal resolution necessary to study a neurotransmitter with rapid release
and clearance kinetics such as glutamate. In order to address this matter, our
laboratory has designed a ceramic-based multisite microelectrode with the
capability to detect and analyze fluctuations in extracellular glutamate
concentrations on a sub-second basis. These microelectrodes were utilized to
study the phasic release and uptake dynamics of potassium-evoked glutamate in
the striatum of young (6 month), late-middle aged (18 month) and aged (24
month) Fischer 344 rats. Our results showed a reduced glutamate clearance
rate and an attenuated response to potassium depolarization in the corticostriatal
projections of aged animals in comparison to other age groups. In addition,
average maximal glutamate release amplitudes were decreased in the striatum
of aged animals. Pressure ejection of exogenous glutamate solution further
confirmed the decreased glutamate clearance ability of the aged striatum. These
potassium and exogenous glutamate data also highlighted a marked
dorsoventral gradient in the striatum in terms of glutamate release and clearance
ability. We further explored this phenomenon of age-related decreased glutamate
uptake by coupling our in vivo technology with classical immunoblotting and
biotinylation techniques in order to investigate glutamate transporter regulation.
Decreased glutamate clearance in the aged rats cannot be attributed to a
reduction in steady-state total transporter protein levels. Rather, our results
indicate that reduced plasma membrane surface trafficking of GLAST in the aged
striatum may be partially responsible for this effect. Finally, we modified our
microelectrodes to study basal glutamate levels in the striatum of the aging,
freely moving rat. This approach allowed us to study extracellular glutamate
regulation free from the potential confounding variable of anesthesia. Our results
demonstrate that there is no significant alteration in basal glutamate levels in
aging in the brain regions investigated. More importantly, this study validated the
efficacy of the utilization of ceramic-based multisite microelectrodes for the study
of alterations in glutamate neurotransmission in the aging, freely moving rat, and
it lays the foundation for future work correlating such changes with age associated
impairments in motor function. |
| URI: | http://hdl.handle.net/10225/81 |
| Appears in Collections: | Electronic Theses and Dissertations
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Files in This Item:
| File |
Description |
Size | Format |
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| JustinNickellDissertation.pdf | | 2389Kb | Adobe PDF | View/Open |
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