A severe health burden imposed by many neuropsychiatric and neurological diseases can be linked to limitations in, or disruption of, molecular pathways which guide development, maintenance or plasticity of synaptic connections. Importantly, as many neural circuits are persistently active the individual synaptic connections must undergo continuous and coordinated homeostatic changes to counteract continual synaptic strengthening/weakening and development of network instability. Thus, developing a functional map of sites of activity- dependent dynamic coordination of the molecules and signaling pathways that define the process is central to enabling an understanding of many CNS diseases. The work proposed is uniquely important as it will elucidate novel and yet potent molecular signaling pathways that mediate accurate and reproducible activity-dependent adaptations in synaptic efficacy. Specifically, investigations focus on understanding how post-synaptic sensing of activity via the mTORC1/BDNF signaling pathway mediates increased presynaptic neurotransmitter release during reduced excitatory input to the post-synaptic element. Investigations will test the hypothesis that tomosyn-1 is a central presynaptic target of mTORC1/BDNF/TrkB receptor signaling and that trans-synaptic adjustments in presynaptic neurotransmitter release via this signaling pathway occur via UPS regulation of tomosyn-1 protein levels. We will also define specific sites within the secretory pathway by which tomosyn exerts control over presynaptic neurotransmitter release. Commonality of this trans-synaptic mechanism will also involve comprehensive evaluation at Mossy fiber/CA3 and at CA3/CA1 synapses of hippocampal brain slices, as these circuits are known to exhibit strikingly divergent synaptic plasticity. In addition, we will characterize the E3 ligase responsible for UPS regulation of tomosyn, determine if the E3 ligase activity is sensitive to mTORC1/BDNF/TrkB signaling and if ubiqutination of tomosyn by the E3 ligase regulates tomosyn protein levels and neurotransmitter release. The investigations employ state of the art optical imaging of vesicle cycling, genetic models targeting protein/signaling function, optogenetic control of neuronal excitability and analysis of synaptic function in cultures of hippocampal neurons and hippocampal slices. Biochemical assays will quantify and establish activity dependent control on tomosyn protein via the UPS. This information will significantly advance understanding on mechanisms by which activity- dependent changes in post-synaptic mTORC1 activity coordinate spatial and temporal adjustments in presynaptic neurotransmitter release.

Public Health Relevance

Fundamental to the brains computational capacity to learn, remember and for imparting behavioral control is its ability to modify the strength of information flow at specific synaptic contacts within astonishingly complex systems of neural networks. Significant links to neurological and neuropsychiatric disorders have now been attributed to genetic disorders and mechanistic deficits in the process by which trans-synaptic communication is tuned and maintained in response to persistent activity. Our work addresses the molecular basis by which communicating neurons dynamically coordinate neurotransmitter release to maintain trans- synaptic stability with the goal being to develop a molecular understanding to better address neurological diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Stewart, Randall R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
Zip Code
Saldate, Johnny J; Shiau, Jason; Cazares, Victor A et al. (2018) The ubiquitin-proteasome system functionally links neuronal Tomosyn-1 to dendritic morphology. J Biol Chem 293:2232-2246
Henry, Fredrick E; Wang, Xiao; Serrano, David et al. (2018) A Unique Homeostatic Signaling Pathway Links Synaptic Inactivity to Postsynaptic mTORC1. J Neurosci 38:2207-2225
Henry, Fredrick E; Hockeimer, William; Chen, Alex et al. (2017) Mechanistic target of rapamycin is necessary for changes in dendritic spine morphology associated with long-term potentiation. Mol Brain 10:50
Cazares, Victor A; Njus, Meredith M; Manly, Amanda et al. (2016) Dynamic Partitioning of Synaptic Vesicle Pools by the SNARE-Binding Protein Tomosyn. J Neurosci 36:11208-11222