# Investigating the role of NLGN3 in autism spectrum disorder and sleep disruptions

> **NIH NIH F31** · BAYLOR COLLEGE OF MEDICINE · 2024 · $48,974

## Abstract

ABSTRACT:
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder that is highly comorbid with sleep
disruptions. Although 40-80% of children diagnosed with ASD exhibit sleep disruptions, the etiology of this
association remains largely unknown. However, through genome wide association studies, it is predicted that
genes regulating neural stability including neurite outgrowth, synapse formation, and synaptic plasticity play an
important role in ASD pathogenesis. One such family of genes that have previously been associated with ASD
is the Neuroligin (NLGN) gene family. NLGNs are a family of postsynaptic cell adhesion molecules that interact
trans-synaptically with neurexins to regulate synapse formation and maturation. Five NLGN genes have been
identified in humans, but only NLGN2, 3, and 4 are classified as high confidence ASD associated genes. All five
genes have unique expression patterns at either y-aminobutyric or glutamatergic synapses; however, only
NLGN3 is expressed in both. Furthermore, individuals with variants in the NLGN3 gene have been identified to
display both ASD and sleep disorders. Three variants of interest are the NLGN3 p.R175W, NLGN3 p.R451C,
and NLGN3 p.R597W as all three variants are associated with ASD and the latter variant is also associated with
sleep disorders. Previous studies have indicated that the NLGN3 p.R451C variant is a gain-of-function allele that
causes mice to exhibit primary phenotypes of ASD and secondary phenotypes of sleep disruption suggesting
that the variant may contribute to both disorders. However, the remaining two variants have yet to be functionally
assessed in vivo. The goal of this proposal is to functionally characterize these variants and identify a molecular
mechanism for the comorbidity between ASD and sleep using a Drosophila model organism. The Drosophila
model organism has a simplified neural circuit, and it has extensively been used to study behaviors associated
with ASD and sleep. Loss-of-function phenotypes associated with the loss of Nlg3, the Drosophila ortholog of
NLGN3 have already been characterized. Nlg3 mutants display a reduction in locomotion, abnormal sleep
consolidation, and an increase in the number of synaptic boutons found at the neuromuscular junction.
Furthermore, Nlg3 mutants are thought to have impaired endocytic behaviors, providing a possible mechanism.
I hypothesize that human NLGN3 variants associated with ASD impairs sleep and vesicle endocytosis. To
accomplish this, we have used a humanization strategy to generate “humanized’ Drosophila lines that express
NLGN3-Ref, NLGN3-R175W, NLGN3-R451C, and NLGN3-R597W cDNAs. We will first determine if human
NLGN3-Reference and variant cDNAs can rescue the loss of fly Nlg3 using behavioral assays to assess for
ASD-associated behaviors and sleep deficits. Then, we will determine if these variants impair endocytosis of
vesicles. This will allow us to determine if NLGN3 variants inhibit endocytosis leading to ...

## Key facts

- **NIH application ID:** 11069899
- **Project number:** 1F31MH139286-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Rebekah Elise Townsley
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2025-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11069899

## Citation

> US National Institutes of Health, RePORTER application 11069899, Investigating the role of NLGN3 in autism spectrum disorder and sleep disruptions (1F31MH139286-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/11069899. Licensed CC0.

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