# Global mapping of altered neural circuits in a mouse model of DDX3X mutations

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $841,057

## Abstract

PROJECT SUMMARY
Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder with dozens of highly penetrant risk
alleles and yet no effective pharmacological treatment. Mutations in the X-linked gene DDX3X are a high-risk
factor for ASD. Affected individuals are predominantly females, so studying DDX3X might offer insights into sex
differences in brain development and function. DDX3X encodes a DEAD-box RNA helicase critical for mRNA
metabolism. DDX3X is broadly expressed, and its functions in the brain are just beginning to emerge: Ddx3x
regulates cortical neurogenesis, hindbrain development, and synaptogenesis. However, we do not know the
circuit-level determinants of DDX3X mutations. There is a critical need to fill these gaps because, until we do so,
deciphering the complexity of ASD and developing effective therapeutics remain out of reach. To address this
unmet need, a mouse with construct and face validity for DDX3X mutations was generated in our laboratory
(Ddx3x+/- mice). The long-term goal is to understand the cellular and circuitry biology of ASD and identify new
targets for therapeutic intervention. The overall objective is to capture the neural mechanisms of mutations in
the ASD risk gene DDX3X with multimodal and holistic profiling. The central hypothesis is that Ddx3x regulates
the molecular identity, connectivity, and activity of corticofugal circuits subserving complex behaviors. The
rationale is that, once we identify reliable neural substrates, mechanism-based therapeutics can be developed
and tested pre-clinically. The hypothesis will be tested by pursuing three Specific Aims: 1) Identify the cortical
populations and the molecular signatures affected in Ddx3x+/- mice; 2) Map brain-wide neural ensembles with
altered connectivity and/or activity in Ddx3x+/- mice; and, 3) Dissect and manipulate corticofugal circuits driving
abnormal behavior in Ddx3x+/- mice. Under Aim 1, the major molecular and cellular ensembles affected by Ddx3x
mutations will be identified using single-cell transcriptomics and 3D cellular mapping. Under Aim 2, activity-based
neural substrates that are disrupted by Ddx3x mutations will be dissected using 3D mapping of immediate-early
genes expression after behavior. Under Aim 3, circuits will be manipulated with chemogenetics approaches. The
proposal is innovative because it uses cutting-edge methods to map the 3D landscape of defined neuronal
populations and whole-brain activity through the entire brain of a novel ASD mouse model. It is also innovative
because DDX3X is a high-confidence risk gene for ASD just recently discovered, and its role on shaping brain
circuits is still completely unknown. The application is significant because it will advance our understanding of
ASD complexity by reaching whole-brain, circuitry-level resolution, while propelling the development of a robust
platform to probe convergences across models and developmental stages. These results are expected to have
a positive...

## Key facts

- **NIH application ID:** 10888997
- **Project number:** 5R01MH131537-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Silvia De Rubeis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $841,057
- **Award type:** 5
- **Project period:** 2023-07-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888997

## Citation

> US National Institutes of Health, RePORTER application 10888997, Global mapping of altered neural circuits in a mouse model of DDX3X mutations (5R01MH131537-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10888997. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*