Access Type

Open Access Dissertation

Date of Award

January 2012

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

Tiffany K. Mathews

Abstract

Many neurological diseases and disorders are a result of alterations with neurotransmitters, neuromodulators, and/or proteins. Specifically, one protein that has been linked to numerous neurological diseases and disorders such as Parkinson's disease, Huntington's disease, addiction, attention deficit hyperactivity disorder (ADHD), and depression is brain-derived neurotrophic factor (BDNF). As a trophic factor, BDNF role is to assist in the growth, survival, and differentiation of neurons. However, there is increasing evidence that BDNF may mediate neurotransmitter dynamics. Our goals were to understand how endogenous BDNF levels and aging modulate the dopamine (DA) dynamics in the mouse striatum. Two complementary neurochemical techniques, slice (in vitro) fast scan cyclic voltammetry (FSCV) and in vivo microdialysis were used to characterize striatal DA dynamics in wildtype and BDNF heterozygous mutant (BDNF+/-) mice.

Overall, our findings highlight that (1) we were able to develop a reliable FSCV assay to characterize DA release-regulating D2 and D3 autoreceptors functionality in the striatum of wildtype (C57BL/6) mice, (2) BDNF+/- mice appear to be hyperdopaminergic at young age, which may be a consequence of reduced DA release and DA transporter functions, (3) perfusion of exogenous BDNF on brain slices from young BDNF+/- mice increases the electrically evoked DA release in a dose-dependent manner, and (4) neurochemically, aged BDNF+/- mice are more similar to their wildtype littermates. Taken together, these results suggest that, during neuronal development, low BDNF levels can modulate DA dynamics, increasing susceptibility to neurological diseases and disorders. However, a life-time of low BDNF levels alone does not appear to be critical in DA dynamics dysregulation with age.

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