# Mechanisms of Synaptic Transmission in Healthy and Disease States

> **NIH NIH R35** · WASHINGTON UNIVERSITY · 2024 · $716,992

## Abstract

Direct examination of presynaptic processes has historically been limited by the resolution constraints of
conventional light microscopy. As a result, much of what we know about vesicle movement, fusion, and
recycling relies on inferences from indirect electrophysiological and/or biochemical assays, or from electron
micrographs that reflect a single instant of a dynamic system. The long-term goal of my research program is to
understand the fundamental mechanisms of synaptic transmission at central synapses, including details of
spatiotemporal dynamics under normal conditions, and what disruptions lead to disease states. Current
projects in the lab address two central knowledge gaps. First, we directly probe and track dynamic presynaptic
processes in living tissue by applying our own novel, nanoscale resolution imaging technology. Using this
approach, we will, for the first time, visualize these processes at the level of single synaptic vesicles within
identified synapses. We have already made significant contributions using this approach, including the
discovery that synaptic vesicle dynamics are active, not passive, and are controlled by actin cytoskeleton and
myosin motors. The second major knowledge gap we address is the contribution of presynaptic deficits to
pathophysiology of Fragile X syndrome (FXS). FXS is the most common known cause of heritable intellectual
disability and autism. Our recent findings have triggered a necessary shift in the field towards considering the
contributions of presynaptic mechanisms in addition to postsynaptic mechanisms, thus creating an entirely new
array of diagnostic and therapeutic possibilities. Continuing work in this area will focus on linking presynaptic
defects with abnormalities at the circuit level and the implications of these abnormalities for behavior and
cognition. Sustained funding through this R35 mechanism will support a multipronged approach to these
important neurobiological questions that will maximize the potential for synergy and translational impact.

## Key facts

- **NIH application ID:** 10828759
- **Project number:** 5R35NS111596-06
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Vitaly A Klyachko
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $716,992
- **Award type:** 5
- **Project period:** 2019-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828759

## Citation

> US National Institutes of Health, RePORTER application 10828759, Mechanisms of Synaptic Transmission in Healthy and Disease States (5R35NS111596-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10828759. Licensed CC0.

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