# Cytoskeletal pathways of cerebellar dysregulation in neurodevelopmental disorders

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $830,168

## Abstract

PROJECT SUMMARY
βII-spectrin, a ubiquitous component of the neuronal cytoskeleton, plays multifaceted roles in the organization
and function of neurons. We recently reported that de novo variants in SPTBN1, which encodes βII-spectrin,
cause a pediatric syndrome characterized by global developmental delay, intellectual disability, ADHD, autism
spectrum disorder (ASD), movement deficits, and epilepsy. However, the neuronal types and pathways that are
most vulnerable to deficits in βII-spectrin function are largely unexplored.
We found that mice with selective loss of βII-spectrin in cerebellar granule cells exhibit symptoms and behaviors
consistent with the clinical presentations observed in individuals carrying pathogenic SPTBN1 variants. The
cerebellum, previously assumed to mostly modulate fine-motor coordination, plays important roles in cognition
and is suspected to contribute to the pathophysiology of neurodevelopmental diseases. Thus, it is important to
define the normal and pathogenic mechanisms modulated by βII-spectrin function in the cerebellum.
To accomplish these goals, we will combine cellular, biochemical, live and super-resolution microscopies, and
electrophysiological techniques with behavioral paradigms to 1) determine the molecular mechanisms underlying
disruption of excitable axonal domains and synaptic transmission in cerebellar granule cells caused by βII-
spectrin deficiencies and 2) leverage novel transgenic mouse models carrying clinically relevant Sptbn1 variants
to assess their effect on cerebellar molecular, cellular, and synaptic function and clinically relevant behaviors.

## Key facts

- **NIH application ID:** 10999606
- **Project number:** 1R01MH136674-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Damaris N Lorenzo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $830,168
- **Award type:** 1
- **Project period:** 2024-08-23 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999606

## Citation

> US National Institutes of Health, RePORTER application 10999606, Cytoskeletal pathways of cerebellar dysregulation in neurodevelopmental disorders (1R01MH136674-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10999606. Licensed CC0.

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