# Mechanisms of Synaptic Transmission in Healthy and Disease States

> **NIH NIH R35** · WASHINGTON UNIVERSITY · 2024 · $233,250

## Abstract

PARENT R35 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:** 10989332
- **Project number:** 3R35NS111596-06S1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Vitaly A Klyachko
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $233,250
- **Award type:** 3
- **Project period:** 2019-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10989332

## Citation

> US National Institutes of Health, RePORTER application 10989332, Mechanisms of Synaptic Transmission in Healthy and Disease States (3R35NS111596-06S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10989332. Licensed CC0.

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