# Synaptic nanostructure and dysfunction in neurodevelopmental disorders

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2024 · $548,062

## Abstract

PROJECT SUMMARY
Neurodevelopmental disorders are a serious health problem affecting more than 3% of children worldwide.
More than 1,000 genetic variants in synaptic proteins are linked to neurodevelopmental disorders such as
autism spectrum disorder (ASD) and schizophrenia. While the symptoms of these disorders differ, each of
them affects transmission between synapses in the brain, altering how information is passed throughout the
neural network. To understand what causes these disorders and how to treat them, researchers are striving to
learn the mechanism behind how these genetic variations affect synaptic function at the cellular and molecular
level. This study aims to help answer foundational questions about synaptic transmission using the emerging
framework of macromolecular assemblies.
Transmitting information efficiently from one synapse to another requires transcellular nanocolumns (TNCs).
TNCs span the synaptic cleft and align the neurotransmitter release site of one neuron with the receptors on a
neighboring neuron. Unfortunately, the arrangement of components within these TNCs remains unclear. This
makes it challenging to determine whether disease-causing mutations disrupt functional TNC formation. This
proposal employs an innovative, multidisciplinary approach that combines cutting-edge cryogenic electron
tomography (cryo-ET), biochemical methods, mass spectrometry, cell imaging and electrophysiological
recordings to generate a nanoscale, macromolecular blueprint of synaptic transmission. Our central hypothesis
is that synaptic proteins form subsynaptic PSD nanoblocks, receptor nanodomains and cleft adhesion
molecule pairs as key building components for TNC alignment and activity dependent re-organization, which is
critical for regulating synaptic transmission and plasticity. Toward proving this hypothesis, the authors have
already used cryo-ET on cultured primary neurons, induced human neurons, and isolated nerve terminals to
directly visualize the nanoscale organization of TNCs in near native state. These efforts have provided the first
molecular-resolution information on such TNC assemblies. Advancing from that success, we will utilize two
independent yet complementary aims to establish the sub-10 nm resolution structure of TNCs in healthy
physiology and diseases: (1) investigate the molecular architecture, composition, and assembly of postsynaptic
nanoblocks, (2) determine the in situ structures of synaptic adhesion molecular pairs and glutamate receptors,
then investigate their organization within the synaptic cleft and their alignment with PSD nanoblocks. This
research will significantly advance scientific understanding of the molecular architecture, dynamics, and
functions of synaptic nanostructures, particularly TNCs. This knowledge will enable development of new
therapeutics that target nanoscale structures.

## Key facts

- **NIH application ID:** 10802861
- **Project number:** 1R01MH132918-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Qiangjun Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $548,062
- **Award type:** 1
- **Project period:** 2023-12-01 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10802861

## Citation

> US National Institutes of Health, RePORTER application 10802861, Synaptic nanostructure and dysfunction in neurodevelopmental disorders (1R01MH132918-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10802861. Licensed CC0.

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