# Mechanisms underlying non-REM sleep and neural oscillation abnormalities in Dup15q and Rett Syndrome: Effects on Intellectual Disability

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $373,350

## Abstract

ABSTRACT
Sleep impairments are ubiquitous in IDDs, and sleep problems profoundly impact quality of life and
neurodevelopmental outcomes. The Center proposes a model research project, focused on the mechanisms
underlying sleep impairments in IDDs using a multidisciplinary approach that includes a clinical component,
animal models, and brain organoid models using patient-derived induced pluripotent stem cells. This project
builds on findings from our previous IDDRC model project and the cells and circuits core, inspired by two striking
findings: (1) in Dup15q syndrome, our investigators discovered profoundly abnormal sleep
physiology, characterized by abnormal sleep spindles and attenuated slow-wave sleep (SWS), among patients
who had undergone overnight clinical, with magnitude of these EEG abnormalities correlated with the degree of
intellectual disability and (2) in Rett syndrome organoid models, our investigators quantified abnormal oscillatory
activity in the earliest stages of development. For this project, we take a fully translational approach to study
mechanisms underlying neural oscillations and sleep in Dup15q and Rett syndrome. In Aim 1 (Clinical), we
verify abnormalities in sleep physiology (SWS and sleep spindle density) in clinical EEGs of young children with
Dup15q syndrome and examine their relation to cognitive function. In Aim 2 (Preclinical model), we examine
sleep physiology (SWS and spindles) and its effect on hippocampal and prefrontal ensemble activity in mouse
models of Dup15q and Rett syndrome, performing EEG and simultaneous electrophysiological recordings and
calcium imaging using a novel miniaturized microscope. In Aim 3 (Preclinical model), we investigate early
neural network function in human cortical, subcortical, and hippocampal organoids from derived from Dup15q
and Rett Syndrome iPSC using calcium imaging, electrophysiological recordings techniques, and transcriptomic
analyses. This project leverages our center's strengths in both clinical and preclinical investigation of syndromic
IDDs and capitalizes on active scientific collaborations between basic and clinical researchers in our center to
understand sleep physiology, a fundamental and understudied problem in IDDs. By verifying the relationship
between NREM sleep abnormalities and behavior in children with these syndromes and then, in model
systems, determining the network and cellular basis of abnormal neural oscillations that are critical for memory
formation and learning, this project will directly inform next steps for development of timely, effective treatments
that may modulate sleep and, in turn, improve neurodevelopmental outcomes.

## Key facts

- **NIH application ID:** 10224910
- **Project number:** 5P50HD103557-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** BENNETT G NOVITCH
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $373,350
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224910

## Citation

> US National Institutes of Health, RePORTER application 10224910, Mechanisms underlying non-REM sleep and neural oscillation abnormalities in Dup15q and Rett Syndrome: Effects on Intellectual Disability (5P50HD103557-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10224910. Licensed CC0.

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