All ETDs from UAB

Advisory Committee Chair

Jacques I Wadiche

Advisory Committee Members

Linda S Overstreet-Wadiche

Lori L McMahon

Lucas Pozzo-Miller

Vladimir Parpura

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Glutamate mediates excitatory synaptic transmission in the central nervous system (CNS). Regulation of glutamate release and uptake shapes the spatiotemporal dynamics of glutamate at and around synapses to influence information transfer between neural cells. This dissertation focuses on the modulation of glutamate release and uptake at excitatory synapses of cerebellar Purkinje cells (PC). In the first project we show that differential expression of PC glutamate transporters controls the amount of glutamate entering the extrasynaptic space, thereby influencing the excitatory responses in surrounding Bergmann glia. This work provides the first evidence that neuronal glutamate uptake affects glial glutamatergic signaling. In the second project, we show that phorbol esters (PEs) can potentiate glutamate release at mature climbing fiber (CF) to PC synapses, an effect that was overlooked in the literature primarily due to postsynaptic receptor saturation. We demonstrate that CF potentiation alters the complex spike in PCs under physiological conditions and we provide evidence that enhanced multivesicular release underlies PE-induced CF potentiation. The results highlight how receptor saturation prevents the detection of increase in neurotransmitter release. They also indicate that PE can bidirectionally modulate synaptic strength, depending on the locus of its action. Together, our results demonstrate fundamental mechanisms that enable precise and dynamic regulation of glutamatergic transmission at CNS synapses.

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