Regulated trafficking of newly synthesized postsynaptic neurotransmitter receptors, ion channels and cell adhesion molecules to their appropriate subcellular domain is critical for establishing, maintaining and altering synaptic strength and connectivity. For example, diverse forms of synaptic plasticity at excitatory synapses are thought to require local synthesis and trafficking of neurotransmitter receptors, which must be processed through multiple organelle networks, classically defined by the endoplasmic reticulum (ER) and Golgi apparatus (GA), to reach their functional destination at synapses. However, little is known about the trafficking route for synaptic proteins leaving the ER at remote sites in dendrites. This issue is especially puzzling considering that the GA, thought to be required for trafficking secreted and integral membrane proteins, is missing from most dendritic branches in mammalian central neurons. Thus, whether secretory molecules are locally trafficked in dendrites, and if so, the identity and spatial distribution of the organelles that mediate local trafficking remain fundamental issues. We will use a combination of novel ER sequestration/release technology coupled with live cell imaging, super resolution microscopy and electrophysiology to visually and functionally track cargo molecules as they travel from the ER to synaptic sites. The proposed experiments will fill a major gap in our understanding of how protein processing, distribution and abundance are controlled within the dendritic secretory network and provide quantitative parameters that can be used to develop, refine, and perhaps challenge current cellular models of synaptic function and plasticity.
Neurons must distribute important molecules responsible for sensing neurotransmitters to the appropriate location at the right time and in the correct amounts for normal function. Tuning where and when these molecules are displayed on the surface of neurons underlies fundamental forms of neural plasticity that are disrupted in numerous neuropsychiatric disorders and diseases. This proposal investigates how proteins are distributed to the appropriate locations in neurons and how this process is influenced by neural activity.
|Hiester, Brian G; Becker, Matthew I; Bowen, Aaron B et al. (2018) Mechanisms and Role of Dendritic Membrane Trafficking for Long-Term Potentiation. Front Cell Neurosci 12:391|