Neurons have been known to have distinct anatomical specifications for over a century. As neurons can have many dendrites and each dendrite can have many synapses it is clear that dendrites are an important modulator of cellular communication and function. How these morphological features modulate cellular function has been a mystery since the time of Cajal's initial observations. Progress has been made in showing that dendrites exhibit chemical compartmentalization. This compartmentalization is exemplified by stimulated changes in Ca++ levels in specific dendritic areas. These features show that dendrites are not homogeneous and indeed not only exhibit morphological heterogeneity but also functional heterogeneity. One of the dominant questions in dendrite biology is how does stimulation of selected regions of dendrites in the intact tissue result in a cellular response? This has been termed dendritic integration with much of its characterization using electrophysiological and Ca++ outputs as indicators of dendritic function. There are however other physiological processes that occur in dendrites with mRNA targeting and local translation that are also important modulators of dendrite-mediated physiologies including synaptic plasticity. Dendritic translation occurs at sites along the length of the dendrites called hotspots first demonstrated simultaneously in the Schuman and Eberwine labs. Recent, in vitro studies from the Eberwine and Kim labs have demonstrated a highly complex dendritic translational process. These data, and those of others, highlight the fundamental need to analyze the temporal and spatial dynamics of translation in dendrites to understand the mechanism of post-synaptic responsiveness and dendritic integration. Much of the translation work to date has utilized dispersed neurons in culture and while appropriate for many experimental questions, it is increasingly clear that cells in their normal microenvironment can be functionally distinct from their in vitro counterparts in their cell biology including RNA expression. Experiments in this application will define the fundamental aspects of multi-mRNA translation in intact dendrites of neurons that are in their natural microenvironment. These data will be the first to quantify the role of the microenvironment in modulating neuronal physiology through modulation of the dynamics of localized dendritic protein synthesis.

Public Health Relevance

The identity of dendrite localized mRNAs in neurons in their natural microenvironment and assessment of their in vivo translational dynamics will be undertaken. The dynamics of simultaneous translation of multiple mRNAs will be studied to provide mechanistic insights as to how in vivo translation may be manipulated with the future goal of developing therapeutic intervention strategies for neurological and neuropsychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM110005-04
Application #
9388369
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Dunsmore, Sarah
Project Start
2015-01-15
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104