# Mutations in ACTL6B cause recessive autism: affected families, mouse model, molecular and circuit mechanisms

> **NIH NIH F99** · STANFORD UNIVERSITY · 2020 · $39,033

## Abstract

Project Summary
Autism spectrum disorder (ASD) is a highly prevalent group of neurodevelopmental disorders whose treatment
efficacy is limited by poor understanding of its causal molecular mechanisms. Identifying disease mechanisms
in ASD involves overcoming several challenges. First, it is difficult to demonstrate causality for a given
mutation, since many mutations increase risk but do not always produce ASD. Second, it is challenging to
identify animal models with autism-related phenotypes that are robust across multiple genetic backgrounds.
Third, limited understanding of the neuronal subtypes and circuits responsible for behavior is a barrier to
studying molecular mechanisms in a disease-relevant cellular context. The proposed research meets all three
of these challenges. In the F99 phase, human families with a highly penetrant form of recessive autism caused
by mutations in ACTL6B, a neuronal-specific subunit of the BAF chromatin remodeling complex, were
identified. Actl6b-/- mice were tested as a model for ACTL6B mutant ASD and found to exhibit autism-related
behaviors on two genetic backgrounds and similar brain anatomy to the affected humans. Transcriptional
analysis of Actl6b-/- cortical cultures indicated that neural activity-induced genes were de-repressed in the
absence of Actl6b, even when action potentials were blocked. The elevated expression of early response
genes, including AP1 transcription factors (e.g., Fos, Junb), in Actl6b-/- neurons was associated with increased
chromatin accessibility at AP1 sites and activity-related transcriptional changes in late-response genes,
implicating abnormal early response gene activation as a potential disease mechanism. The genomic
localization of the BAF complex, AP1 transcription factors, and the NCoR complex, which interacted with BAF
in cortical tissue, will be studied in wildtype and Actl6b-/- neurons to learn if altered targeting of these
complexes may contribute to disease-related transcriptional changes. To gain insight into the affected neuronal
circuitry, a serotonin receptor 1b (5HT1b) agonist that was shown to rescue social behavior in the 16p11
autism mouse model (PMID: 30089910) was tested and found to rescue social impairments in Actl6b-/- mice.
Serotonergic neuron-specific deletion of Arid1b, the most frequently mutated BAF subunit in autism, caused
social impairments in mice that could likewise be rescued with the 5HT1b agonist, indicating that BAF function
in serotonergic neurons is critical for social behavior. These studies have inspired the postdoctoral (K00)
research direction: to interrogate autism-related molecular mechanisms within neuronal populations that
control behavior. The postdoctoral training in systems neuroscience will buoy future studies linking the
functions of chromatin regulatory proteins directly to behavior. This research supports the missions of the
NIH Blueprint and BRAIN Initiative by providing new tools for autism research and revealing molecular ...

## Key facts

- **NIH application ID:** 10071836
- **Project number:** 1F99NS118735-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Wendy Wenderski
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $39,033
- **Award type:** 1
- **Project period:** 2020-09-09 → 2022-03-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071836

## Citation

> US National Institutes of Health, RePORTER application 10071836, Mutations in ACTL6B cause recessive autism: affected families, mouse model, molecular and circuit mechanisms (1F99NS118735-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10071836. Licensed CC0.

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