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Published on: October 17, 2025
Deletion of CTNNB1 in inhibitory circuitry contributes to autism-associated behavioral defects
Fengping Dong1, Joanna Jiang1, Colleen McSweeney1
1Department of Biology, Pennsylvania State University, University Park, PA 16802, USA.
Abstract:
Mutations in β-catenin (CTNNB1) have been implicated in cancer and mental disorders. Recently, loss-of-function mutations of CTNNB1 were linked to intellectual disability (ID), and rare mutations were identified in patients with autism spectrum disorder (ASD). As a key regulator of the canonical Wnt pathway, CTNNB1 plays an essential role in neurodevelopment. However, the function of CTNNB1 in specific neuronal subtypes is unclear. To understand how CTNNB1 deficiency contributes to ASD, we generated CTNNB1 conditional knockout (cKO) mice in parvalbumin interneurons. The cKO mice had increased anxiety, but had no overall change in motor function. Interestingly, CTNNB1 cKO in PV-interneurons significantly impaired object recognition and social interactions and elevated repetitive behaviors, which mimic the core symptoms of patients with ASD. Surprisingly, deleting CTNNB1 in parvalbumin-interneurons enhanced spatial memory. To determine the effect of CTNNB1 KO in overall neuronal activity, we found that c-Fos was significantly reduced in the cortex, but not in the dentate gyrus and the amygdala. Our findings revealed a cell type-specific role of CTNNB1 gene in regulation of cognitive and autistic-like behaviors. Thus, this study has important implications for development of therapies for ASDs carrying the CTNNB1 mutation or other ASDs that are associated with mutations in the Wnt pathway. In addition, our study contributes to a broader understanding of the regulation of the inhibitory circuitry.
Insights
Loss-of-function mutations in beta-catenin (CTNNB1) impact neurodevelopment. Deleting CTNNB1 in specific brain cells caused autistic-like behaviors and altered cognitive functions in mice.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Mutations in beta-catenin (CTNNB1) are linked to various disorders, including intellectual disability and autism spectrum disorder (ASD).
- CTNNB1 is crucial for the canonical Wnt pathway and neurodevelopment, but its role in specific neuronal subtypes remains unclear.
Purpose of the Study:
- To investigate the cell type-specific function of CTNNB1 in neurodevelopment and its contribution to ASD.
- To understand how CTNNB1 deficiency in parvalbumin interneurons affects cognitive and behavioral phenotypes.
Main Methods:
- Generation of CTNNB1 conditional knockout (cKO) mice specifically in parvalbumin (PV)-expressing interneurons.
- Behavioral analyses including anxiety, motor function, object recognition, social interaction, repetitive behaviors, and spatial memory tests.
- Assessment of neuronal activity using c-Fos expression in different brain regions.
Main Results:
- CTNNB1 cKO mice exhibited increased anxiety, impaired object recognition, social interaction deficits, and elevated repetitive behaviors, mimicking core ASD symptoms.
- Spatial memory was unexpectedly enhanced in CTNNB1 cKO mice.
- Reduced c-Fos expression was observed in the cortex, but not the dentate gyrus or amygdala, indicating altered neuronal activity.
Conclusions:
- CTNNB1 plays a cell type-specific role in regulating cognitive functions and autistic-like behaviors.
- These findings highlight the importance of CTNNB1 in inhibitory circuitry and neurodevelopment.
- The study offers potential therapeutic targets for ASDs associated with CTNNB1 or Wnt pathway mutations.
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