Dynamic Control of Local Synaptic-Membrane Protein Composition by the Dendritic Secretory Pathway

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 DESCRIPTION (provided by applicant): During learning and memory formation, synaptic connections between neurons are selectively reorganized based on patterns of neural activity in a process called "synaptic plasticity". Underlying this phenomenon is the precise, regulated delivery of synaptic proteins, such as neurotransmitter receptors, adhesion molecules and ion channels that modify synaptic strength and cellular excitability in response to activity. Local translation has emerged as an important mechanism that facilitates protein delivery to dendritic locations long-distances from the neuronal soma. A diverse array of soluble and integral-membrane proteins are locally synthesized, including glutamate receptor subunits and neuroligins that are important for certain forms of synaptic plasticity. However, the delivery of integral-membrane proteins is complicated by the fact that they require not just the machinery for protein synthesis, but also trafficking through the entire complement of secretory organelles to reach the cell surface. Studies characterizing the dendritic secretory organelles have revealed that many of the post-endoplasmic reticulum (ER) organelles, such as Golgi Complex, are scarce within the dendrite and their functional significance unclear. Consequently, it is unknown whether locally translated proteins undergo delivery to nearby areas of the dendritic membrane, or if there are specific signals that control their delivery. This proposal addresses the hypothesis that the distribution of synaptic cargo within the dendritic early secretory pathway spatially defines its delivery to the dendritic plasma membrane and that synaptic activity is a key regulatory of this process. I will investigate thhis hypothesis by tracking synaptic proteins as they traffic from the dendritic ER (the site of local synthesis for membrane proteins) to the plasma membrane to determine the range and kinetics of their delivery. The results will reveal whether the secretory pathway exerts spatial and temporal control of trafficking in order to direct cargo to specific dendritic locations, thus selectively modifying certain synapses. Overall, the findings will provide a foundation to understand the contribution of the secretory pathway to fundamental aspects of normal cognition, as well as how perturbed secretory trafficking may lead to cognitive dysfunction in a wide variety of diseases and disorders, including Alzheimer's disease, developmental delay, Huntington's disease, and autistic disorders.