# Molecular mechanisms of target-specific synapse formation

> **NIH NIH R56** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $540,915

## Abstract

Proper brain function requires that neurons make specific types of synapses with specific types of target
neurons. Defects in this process of synapse specficity can alter brain activity and may underlie many
types of mental illnesses but we know little about the mechanisms by which synapse specificity develops.
We recently discovered that the cell adhesion molecule Kirrel3, which is a risk factor for autism and
intellectual disability and other mental illnesses, is selectively required for formation of a specific type of
hippocampal synapse that connects DG neurons to GABA neurons. This synapse provides feed-forward
inhibition to CA3 and Kirrel3 null mice have significantly elevated CA3 neuron activity. This established
Kirrel3 as a functionally relevant target-specific synaptogenic molecule but we still do not know the
mechanism of how it functions. Through a series of in vitro assays, our new preliminary data suggests
that Kirrel3 binds other Kirrel3 molecules in cis and trans, functions directly in pre- and post-synapse
formation, and requires yet to be identified neuron-specific binding partner(s). In the hippocampus, Kirrel3
is only expressed by DG and GABA neuron. Thus, we will test the central hypothesis that homophilic,
trans-cellular Kirrel3 interactions nucleate DG-to-GABA synapses by sending bi-directional signals to
actively recruit pre- and post-synaptic proteins. In Aim 1, we will determine if Kirrel3 function requires
trans-cellular binding in vivo by determining precisely where, when, and how much Kirrel3 is required to
build hippocampal DG-to-GABA synapses. In Aim 2, we will define the role of Kirrel3 in adhesion versus
synapse formation and identify binding partners and downstream signaling mechanisms mediated by
Kirrel3. Kirrel3 provides a new approach to identify the still elusive mechanisms of target-specific synapse
formation and, given its links to disease, our results will provide basic insight to the etiology of cognitive
and mental illnesses.

## Key facts

- **NIH application ID:** 10048898
- **Project number:** 2R56MH105426-06
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Megan Elise Williams
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $540,915
- **Award type:** 2
- **Project period:** 2014-09-25 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10048898

## Citation

> US National Institutes of Health, RePORTER application 10048898, Molecular mechanisms of target-specific synapse formation (2R56MH105426-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10048898. Licensed CC0.

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