# Molecular Mechanisms Underlying the sex-Depended Maturation of Modulatory Systems.

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $570,144

## Abstract

PROJECT SUMMARY/ABSTRACT
Males are diagnosed with autism spectrum disorder (ASD) at least four times as frequently as females, but the
molecular underpinnings of male predominance remain elusive. Serotonergic (5-HT) neurons in the raphe nuclei
(RN) extend axonal projections throughout the brain and regulate many essential brain function, including social
behaviors. Importantly, abnormal development of the 5-HT system has been described in ASD. 5-HT signaling
in the brain differs in males and females, but molecular mechanisms regulating sex-dependent 5-HT synaptic
function are largely unknown. The overarching goal of this proposal is to elucidate molecular mechanisms
underlying sex-dependent 5-HT synapse development and function, and determine sex-dependent effects of 5-
HT on social behavior by focusing on the trans-synaptic molecules Neurexins (Nrxns), a well-accepted risk factor
for neurodevelopmental disorders, including ASD.
 The formation and regulation of synapses are fundamental biological processes in brain development and
function. These events require trans-synaptic protein-protein interactions to functionally regulate pre- and
postsynaptic structures that determine synaptic function. Neurexins (Nrxns) are presynaptic cell-adhesion
molecules and involved in synapse formation and regulation through trans-synaptic protein interactions with
postsynaptic adhesion molecules such as neuroligins. Importantly, Nrxn and 5-HT mutant mouse models display
deficits in social cognitive behaviors which are reminiscent of ASD. Despite evidence that synapse specification
relies on Nrxn function and that appropriate 5-HT signaling impacts social cognitive behaviors, the role of Nrxns
in 5-HT synaptic transmission and sex-dependent Nrxn functions is unknown.
 Our central hypothesis is that the 5-HT system undergoes sex-specific modulation or development. To
test this hypothesis, we will identify how Nrxn proteins specifically shape the development and function of the 5-
HT system in males and females. This will reveal a previously unexplored 5-HT system architecture that shapes
5-HT neurotransmission and behavior. We will determine i) Nrxn gene(s) important for sex-dependent
development of 5-HT release in the RN and hippocampus (Aim 1), ii) Nrxn gene(s) important for sex-dependent
development of 5-HT system structure in the hippocampus (Aim 2), and iii) Nrxn gene(s) important for sex-
dependent social behavior (Aim 3).
 We anticipate that our investigation of sex-specific consequences of abnormal 5-HT signaling will profoundly
advance our understanding of sex-specific behaviors. Our work should thus contribute to the elucidation of the
molecular mechanisms that contribute to the male prevalence of ASD, as well as identify novel therapeutic
targets to treat cognitive behavioral deficits in neurodevelopmental and neuropsychiatric disorders such as ASD.

## Key facts

- **NIH application ID:** 10892119
- **Project number:** 5R01MH130582-03
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** KENSUKE FUTAI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $570,144
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892119

## Citation

> US National Institutes of Health, RePORTER application 10892119, Molecular Mechanisms Underlying the sex-Depended Maturation of Modulatory Systems. (5R01MH130582-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10892119. Licensed CC0.

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