Diversity of Presynaptic Function Among Neuronal Populations

Cedars-Sinai Medical Center, West Hollywood CA

Investigators

Abstract

ABSTRACT Tight regulation of neurotransmitter release is critical for normal brain function. After decades of research, we understand the general mechanism of this process, but this reflects the average synapse. The brain uses a variety of neurotransmitters that differ in the architecture of the release site, the time scale of signaling and the effect they have on the activity of the target cell with less understanding of differences in corresponding presynaptic regulatory mechanisms. We compared the subcortical glutamate system that assures fast and reliable rely of information with dopamine neurons that release a slow acting modulatory transmitter in a frequency dependent manner. We found that the release of these two transmitters differs in frequency dependence and that dopamine and glutamate are stored in functionally distinct synaptic vesicles even if released from the same neuron. Further comparison of the vesicles that store monoamines or glutamate by mass spectrometry revealed differences in protein composition. The proposed research aims to understand how differences in presynaptic machinery affect the properties of dopamine and glutamate release. We will address the role of SV replenishment pathways in generating molecular diversity in synaptic vesicle composition and function. Also, since SV replenishment after fusion includes poorly understood quality control steps that include decisions regarding the reuse or degradation of SV proteins, we will focus on cell type and SV retrieval pathway dependent differences in protein homeostasis machinery at the presynaptic terminal. Altogether, this project will provide insight into presynaptic function in monoamine neurons and increase our understanding of the molecular factors that regulate neurotransmitter release probability. The proposal also addresses a likely diversity in the mechanisms of presynaptic protein homeostasis and has the potential to reveal sources of selective vulnerability of monoamine neurons in neurodegeneration.