Transmission of information through neural circuits at synapses is an essential requirement for cognition, learning, memory, and motor function. Synaptic transmission is not fixed but dynamically modifiable, a process referred to as synaptic plasticity. Exocytosis of synaptic vesicles is mediated by the SNARE family proteins which form trans-SNARE complexes between the vesicle and presynaptic plasma membrane. Formation of these SNARE complexes serves as a central regulated molecular mechanism underlying the efficacy of synaptic transmission. Tomosyn is a unique presynaptic R-SNARE protein in that it is cytosolic and serves as a potent negative regulator of exocytosis. The availability and activity-state of tomosyn in nerve terminals affects release probability by negatively regulating the priming of vesicles for release. What remains unknown are the molecular mechanisms and signaling pathways by which tomosyn activity is modulated. Provocative recent evidence suggests that the ubiquitin (Ub) and small ubiquitin-like modifier (SUMO) pathways exert particularly important influences on the modulation of synaptic strength. Remarkably, my preliminary evidence indicates that tomosyn protein levels and activity are subject to regulation by these distinct post-translational modifications. Therefore, I hypothesize that tomosyn's affects on synaptic plasticity are under dynamic modulation of the activity of these systems. I propose to test this hypothesis by employing a combination of genetic manipulations, biochemistry, fluorescence imaging, and electrophysiological measurements to delineate: 1) if tomosyn is subject to regulated degradation via the ubiquitin proteasome system (UPS), and 2) how sumoylation of tomosyn modulates its sub-cellular localization, protein-protein interactions, and functional activity. Specifically, these aims will determine the synaptic activity states that indue post-translational modification of tomosyn via Ub and SUMO, define the relationship between these modifications and changes in tomosyn's mechanism of activity, and link these activity alterations to functional changes in presynaptically- mediated plasticity induction. Successful completion of these aims will reveal novel insights into how neural plasticity is induced and regulated, including the effects by which, and extent of, tomosyn involvement in neural activity-induced changes in presynaptic plasticity and homeostasis. Data gathered will extend beyond basic science research by providing potential mechanistic targets for preventative and therapeutic approaches for diseases involving neurotransmission, including those recently linked to tomosyn- and UPS-mediated alterations in neurotransmission and human central nervous system function and health (e.g. autism-spectrum disorders and Alzheimer's disease).

Public Health Relevance

Information transfer in the brain occurs at contact points between neurons (termed synapses) and is absolutely essential for cognition, learning, memory, and motor functions. Transmission of information occurs in the form of electrical and chemical signaling within and between cells and, importantly, this process is not fixed, but varies in strength as a function of circuit activity (termed synaptic plasticity). My research is aimed at defining molecular components and pathways that govern synaptic plasticity in the presynaptic compartment, with the rationale that improper synaptic plasticity results in deficiencies of mental health and cognitive states, including some forms of cognitive impairment, dementia, and neurodegeneration. Understanding how synaptic transmission occurs allows for a more complete understanding of: 1) the process of information transfer and storage, and 2) certain deficient cognitive states, which serves as a necessary foundation for development of effective treatment and prevention methods.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Stewart, Randall R
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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