# Dynamic control of synapse organization and function by cleft-resident molecules

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $565,617

## Abstract

The synaptic cleft is a conserved and integral component of central synapses. It is comprised of protein
complexes that span across it, and their adhesive interactions and signaling roles guide synapse development.
Their relevance is underscored by the mutations in synapse-organizing proteins that are linked to complex
brain disorders including autism-spectrum disorders and schizophrenia. Yet, the molecular patterning and
dynamics of synaptic cleft components remain largely unknown. This contrasts with our understanding of the
nanoscale organization of pre- and post-synaptic compartments, which is elucidating our understanding of
synaptic structure and function. Moreover, acute synapse-organizing roles of cleft proteins at mature synapses
and the functional interplay of trans-synaptic interaction systems remain to be defined. Our central hypothesis
is that the properties and plasticity of mature synapses are dynamically instructed by select cleft components.
This proposal builds on preliminary and previously published results by the collaborating groups that synaptic
adhesion complexes are differentially localized within the cleft, shape this compartment, can undergo rapid
changes in synaptic abundance upon plasticity induction, and alter long-term synaptic plasticity. Three specific
aims will be pursued to test our hypothesis. First, we will test roles of trans-synaptic interactions in acutely
instructing pre- and postsynaptic function. Second, it is our aim to determine the molecular and organizational
dynamics of the cleft during long-term plasticity. Third, we will identify cleft proteins that guide changes during
plasticity. Our approaches include tools to acutely perturb trans-synaptic interactions, proximity labeling to
identify cleft-resident molecules and monitor them during plasticity, superresolution imaging to map their cleft
locations, and cell biological and physiological functional assays. We anticipate to determine the molecular
patterning and dynamics of the synaptic cleft and to identify how trans-synaptic interactions actively shape
synaptic function. This expected progress is significant because it will define the cleft as a molecularly
organized and acutely controlled cellular compartment that instructs synaptic properties. Moreover, this
research can determine how a dynamic remodeling of the cleft architecture underlies the activity-dependent
plastic changes at synapses. Synaptic organization and function are disrupted in neurodevelopmental and
neurological disorders, and this program will provide information for defining how these diseases impact the
cleft and may even originate in it to alter synaptic properties.

## Key facts

- **NIH application ID:** 10138150
- **Project number:** 7R01MH119826-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Thomas Biederer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $565,617
- **Award type:** 7
- **Project period:** 2019-03-06 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10138150

## Citation

> US National Institutes of Health, RePORTER application 10138150, Dynamic control of synapse organization and function by cleft-resident molecules (7R01MH119826-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10138150. Licensed CC0.

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