# The role of Neurexin in serotonin synaptic function and social behavior

> **NIH NIH F30** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $33,398

## Abstract

PROJECT SUMMARY/ABSTRACT
The goal of this proposal is to examine how presynaptic Neurexins (Nrxns) at serotonin (5-HT) synapses
impact 5-HT signaling and social behavior. Extensive 5-HT axon terminal innervation throughout the brain
corroborates 5-HT’s modulatory role in numerous behaviors including social behaviors, reward, emotion
regulation, and learning and memory. Abnormal brain 5-HT levels and function are implicated in Autism
Spectrum Disorder (ASD). While 5-HT therapeutics are often used to treat ASD, variable improvements in
symptomatology require further investigation of 5-HT-mediated pathology. Many different genes contribute to
increased ASD susceptibility and clinical presentation variability. Notably, synaptic dysfunction, specifically
dysregulation of synaptic excitation and inhibition, remains a hallmark of ASD pathogenesis. Nrxns are
presynaptic cell adhesion molecules that are well characterized in maintaining synapse function for proper neural
circuit assembly. The three Nrxn genes transcribed from two promoters (α and β) express six principal Nrxn
isoforms (αNrxn1-3, βNrxn 1-3). Additionally, mutations in Nrxn1 and Nrxn2 genes have been reported in ASD.
In the current literature, the role of Nrxns at 5-HT synapses has yet to be investigated. Given that aberrant Nrxn
and 5-HT function independently contribute to signaling pathology and social behavior impairments, it is critical
to understand how Nrxn-mediated 5-HT neurotransmission participates in pathological mechanisms underlying
the core deficits of ASD.
 Here, I will explore how 5-HT signaling mediated through Nrxns regulates social behaviors (Aim 1) and
how Nrxns regulate 5-HT circuits relevant to social behaviors (Aim 2). Our group has created a novel mouse
model in which the three Nrxn genes are selectively deleted in 5-HT neurons. My preliminary studies indicate
that the loss of Nrxns at 5-HT synapses impairs social recognition memory and social reward preference. The
hippocampus and nucleus accumbens, respectively, are crucial in these behaviors. In Aim 1, I will determine
whether 5-HTergic Nrxns are critical for social behaviors through completion of social (and other complex)
behavior studies. In addition, I will explore (i) if and (ii) how 5-HT is necessary for social behaviors using (i) 5-HT
therapeutics to augment 5-HT function prior to social behavior studies and (ii) in vivo microdialysis to measure
extracellular 5-HT levels during social behavior. In Aim 2, I will perform a mouse breeding and lentiviral rescue
approach to determine whether specific Nrxns control social behavior. Furthermore, I will use
immunohistochemical and electrophysiological approaches to identity how Nrxn proteins regulate excitatory and
inhibitory synapse distribution and physiology. A close examination of Nrxns in 5-HT synaptic function is
necessary to shed new light on social behavior disturbances in ASD.

## Key facts

- **NIH application ID:** 10165487
- **Project number:** 5F30MH122146-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Amy Cheung
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $33,398
- **Award type:** 5
- **Project period:** 2020-05-11 → 2025-05-10

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165487

## Citation

> US National Institutes of Health, RePORTER application 10165487, The role of Neurexin in serotonin synaptic function and social behavior (5F30MH122146-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10165487. Licensed CC0.

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