The strength of synaptic connections plays a critical role in determining information flow within neural circuits and establishing how circuits can be modified in response to changing inputs. A key parameter of synaptic strength is the probability of neurotransmitter release from the presynaptic neuron. Neurotransmitter release depends on localized calcium influx triggering fusion of molecularly primed synaptic vesicles at specialized domains of presynaptic terminals called active zones. We and others have found that conserved proteins of the active zone cytomatrix regulate key determinants of release probability, including the number of release- ready synaptic vesicles, calcium channels clustering, and the spatial coupling of vesicles and channels. Presynaptic release properties vary considerably even between neighboring AZs of the same neuron. Yet, how proteins of the conserved AZ cytomatrix act locally to generate a diversity of synaptic strengths is not understood. Emerging observations, including our own preliminary data, indicate that AZ cytomatrix proteins are differentially deployed at functionally distinct synapses, suggesting a flexible strategy for achieving functional diversity. Here, we build on our advances in understanding local determinants of synaptic function to elucidate how active zones are organized to achieve synapse-specific neurotransmitter release properties (Aim 1), how synapses are reorganized during plasticity (Aim 2), and how functional heterogeneity interacts with plasticity to support circuit function in response to changing inputs (Aim 3).

Public Health Relevance

To support complex behavior, neural circuits, the functionally connected neurons that give rise to thought and behavior, must be both reliable and flexible. The proposed research extends our advances in understanding the molecules that organize synaptic connections for robust communication to determine how synapses with distinct properties are established and the role of synaptic diversity in allowing circuits to respond to a broad range of changing inputs. Successful completion of our aims will advance understanding of how synapses are organized to support robust and adaptable neural function, and how these processes can be disrupted in diseases states.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Miller, Daniel L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brown University
Schools of Medicine
United States
Zip Code
Bruckner, Joseph J; Zhan, Hong; Gratz, Scott J et al. (2017) Fife organizes synaptic vesicles and calcium channels for high-probability neurotransmitter release. J Cell Biol 216:231-246
Zhan, Hong; Bruckner, Joseph; Zhang, Ziheng et al. (2016) Three-dimensional imaging of Drosophila motor synapses reveals ultrastructural organizational patterns. J Neurogenet 30:237-246
O'Connor-Giles, Kate (2016) Toll-tally tubular: A newly identified Toll-like receptor-FoxO pathway regulates dynamics of the neuronal microtubule network. J Cell Biol 214:371-3
Ukken, Fiona P; Bruckner, Joseph J; Weir, Kurt L et al. (2016) BAR-SH3 sorting nexins are conserved interacting proteins of Nervous wreck that organize synapses and promote neurotransmission. J Cell Sci 129:166-77
Gratz, Scott J; Harrison, Melissa M; Wildonger, Jill et al. (2015) Precise Genome Editing of Drosophila with CRISPR RNA-Guided Cas9. Methods Mol Biol 1311:335-48
Gratz, Scott J; Rubinstein, C Dustin; Harrison, Melissa M et al. (2015) CRISPR-Cas9 Genome Editing in Drosophila. Curr Protoc Mol Biol 111:31.2.1-20
Bruckner, Joseph J; Zhan, Hong; O'Connor-Giles, Kate M (2015) Advances in imaging ultrastructure yield new insights into presynaptic biology. Front Cell Neurosci 9:196
Harrison, Melissa M; Jenkins, Brian V; O'Connor-Giles, Kate M et al. (2014) A CRISPR view of development. Genes Dev 28:1859-72
Gratz, Scott J; Ukken, Fiona P; Rubinstein, C Dustin et al. (2014) Highly specific and efficient CRISPR/Cas9-catalyzed homology-directed repair in Drosophila. Genetics 196:961-71
Gratz, Scott J; Cummings, Alexander M; Nguyen, Jennifer N et al. (2013) Genome engineering of Drosophila with the CRISPR RNA-guided Cas9 nuclease. Genetics 194:1029-35

Showing the most recent 10 out of 11 publications