Date

7-2015

Document Type

Dissertation

Institution

Oregon Health & Science University

Abstract

Information is transmitted between neurons through a process known as synaptic transmission. We are resolved to study synaptic transmission as an effort to understand the workings of the brain. There has been considerable effort into understanding synaptic transmission mediated by glutamate, GABA, and acetylcholine. Much less emphasis has been on synaptic transmission mediated by monoamine neurotransmitters, dopamine, noradrenaline, and serotonin, despite their critical role in physiology.

The goal of this dissertation is to advance the understanding of dopaminedependent synaptic transmission. It is established that dopamine neurons in the ventral midbrain release dopamine from the somatodendritic compartment. Once released, dopamine activates G protein-coupled dopamine D2 receptors on neighboring dopamine neurons. Activated D2 receptors negatively regulate dopamine release locally and in extensive axon terminal projection areas. Ultimately, somatodendritic dopamine transmission affects dopamine-dependent processes throughout the brain. However, many aspects of the regulation of somatodendritic dopamine transmission are controversial, arising from an incomplete understanding of the somatodendritic dopamine synapse.

Through electrophysiological recordings and immunohistochemical studies in acute mouse brain slices, this work examines the presynaptic and postsynaptic components of the dopamine synapse, as well as their proximity. Work presented in this dissertation describes spontaneous D2 receptor-mediated inhibitory postsynaptic currents (D2-IPSCs) produced by action potential-independent exocytosis of dopamine-filled vesicles and the subsequent activation of a D2 receptor-dependent G protein-coupled inwardly rectifying potassium conductance. The results reveal that dopamine release sites and D2 receptors are closely apposed, which allows for temporal and spatial specificity in dopamine signaling despite the slow intrinsic signaling kinetics of G protein-coupled receptors. Moreover, spontaneous dopamine synaptic events alter dopamine neuron excitability, as observed by transient inhibitions in action potential firing that were dependent on vesicular release of dopamine and activation of D2 receptors.

The occurrence of spontaneous D2-IPSCs was then leveraged to advance the understanding of the presynaptic and postsynaptic components of the somatodendritic dopamine synapse. The origins of dopamine release was investigated through comparisons of spontaneous and electrically evoked synaptic events. These results revealed an unexpected and robust contribution of serotonin terminal-derived dopamine to D2 receptor-dependent signaling after in vivo or in vitro exposure to the dopamine precursor, L-DOPA. Under basal conditions, the results are most consistent with dopamine release occuring strictly from neighboring dopamine neurons. The characteristics and regulation of postsynaptic D2 receptors were also studied. When virally expressed, either splice variant of the D2 receptor, D2S or D2L, was capable of producing spontaneous D2-IPSCs. Contrary to the canon, the results suggested that both splice variants may function as somatodendritic autoreceptors in wild type dopamine neurons. Lastly, the study of spontaneous D2-IPSCs aided in the assessment of somatodendritric dopamine signaling pertrubations in a mouse line that harbors a diseaseassociated mutation in the dopamine transporter.

In conclusion, the investigation of spontaneous D2 receptor-mediated IPSCs revealed insights into the structure of the dopamine synapse and the regulation of evoked and spontaneous dopamine transmission, and dopamine neuron excitability. More broadly, their occurrence demonstrated that many of the defining features of ionotropic receptor- and G protein-coupled receptor-dependent synaptic transmission are similar.

Identifier

doi:10.6083/M45X27XF

Division

Neuroscience Graduate Program

School

School of Medicine

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