# Synaptic Organizers: Dynamic Regulation of Trans-synaptic Bridges

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2022 · $511,367

## Abstract

The synaptic organizers, α-neurexins, form macromolecular bridges with their post-synaptic partners that
span the synaptic cleft (‘trans-synaptic bridges’); together they play a crucial role in mediating synaptic
connections and communication between neurons. α-Neurexins and their partners are implicated in
neurological disorders including autism spectrum disorder, schizophrenia and mental retardation.
α-Neurexin trans-synaptic bridges have traditionally been considered static. However, there is
accumulating evidence that they are in fact dynamically regulated! Dynamic regulation of α-neurexin trans-
synaptic bridges is important, because it means that the synapse-promoting role of α-neurexins is tunable and
can be increased or decreased at a particular synapse. Three very different mechanisms have recently been
revealed that control the trans-synaptic bridges between α-neurexins and their partners: 1) competing decoys,
2) proteins secreted by astrocytes, and 3) allosteric modulation of α-neurexin binding partners. However, it is
not known on a molecular level how these mechanisms work. It is essential to determine the molecular bases
that underlie these regulatory mechanisms, because they not only control the synapse-promoting activity of 
α-neurexins, but they also involve protein interactions that could be targeted to manipulate specific synaptic
connectivities and exploited therapeutically.
 In this proposal, we will determine the molecular bases of three mechanisms that control the formation of
α-neurexin trans-synaptic bridges. We hypothesize that these different molecular mechanisms exploit unique
elements in the 3D structure of α-neurexins and their partners to generate platforms that permit dynamic
regulation. We will use structural, biophysical and biochemical techniques to elucidate mechanisms involving
1) competing synaptic organizers, 2) astrocytic factors, and 3) allosteric modulation. Collectively, our results
will reveal on a molecular level how regulatory mechanisms mold α-neurexin trans-synaptic bridges impacting
synapse development and synaptic communication. This proposal is significant because genetic lesions in 
α-neurexins and their partners are involved in the pathogenesis of severe neurological disorders, so mechanisms
regulating their interactions and functions, control their contribution to disease as well. This work will also set
the stage for developing mechanism-based, focused therapies to address specific CNS disorders. This
proposal is conceptually innovative because it will help establish the emerging paradigm shift that trans-
synaptic bridges formed by synaptic organizers, like α-neurexins and their partners, are in fact subject to
intense regulation and their ability to stabilize synaptic function is rendered tunable by other interacting
proteins. This proposal is also technically innovative because it involves single particle electron tomography
for which we are actively developing methodologies to image synap...

## Key facts

- **NIH application ID:** 10397995
- **Project number:** 5R01MH077303-16
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Gabrielle Rudenko
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $511,367
- **Award type:** 5
- **Project period:** 2006-04-01 → 2023-12-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10397995

## Citation

> US National Institutes of Health, RePORTER application 10397995, Synaptic Organizers: Dynamic Regulation of Trans-synaptic Bridges (5R01MH077303-16). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10397995. Licensed CC0.

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