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Deciphering the role of CAPZA2 in neurodevelopmental disorders: insights from mouse models

Summary

Scientists studied a gene called CAPZA2 that helps control how brain cells connect to each other. When this gene doesn’t work properly, mice had trouble learning, remembering things, and interacting socially, similar to intellectual disability in humans. The researchers found that the problem happens because the connections between brain cells become abnormal and don’t mature properly. This research helps explain why some people with mutations in this gene have developmental difficulties and could lead to new treatments.

Background

Intellectual disability affects 1-3% of the global population with many unidentified genetic causes. Recent clinical studies have identified mutations in the CAPZA2 gene, which encodes an actin cytoskeleton regulator, as potential contributors to neurodevelopmental disorders. The protein plays a crucial role in dendritic structure and synaptic plasticity during brain development.

Objective

This study investigates the role of CAPZA2 in neurodevelopmental disorders using two distinct mouse models: CAPZA2 heterozygous knockout (CAPZA2 +/−) and heterozygous point mutant (CAPZA2 c.G776T/+) mice. The goal is to establish causal relationships between CAPZA2 mutations and intellectual disability while exploring underlying molecular mechanisms.

Results

Both CAPZA2 +/− and CAPZA2 c.G776T/+ mice demonstrated significant reductions in CAPZA2 expression in hippocampus and prefrontal cortex, along with motor dysfunction, anxiety-like behaviors, and impairments in spatial and non-spatial memory. Morphological analyses revealed increased dendritic spine density with altered morphology in hippocampus and decreased dendritic complexity in prefrontal cortex, with dysregulation of synaptic proteins including PSD95 and glutamate receptors.

Conclusion

CAPZA2 deficiency impairs synaptic structure and disrupts synaptic protein expression, leading to cognitive and behavioral abnormalities. The study provides strong evidence for the causal relationship between CAPZA2 mutations and neurodevelopmental disorders, revealing its critical role in brain development and function with potential implications for understanding and treating intellectual disability.
  • Published in:Communications Biology,
  • Study Type:Animal Model Study,
  • Source: PMID: 40659881, DOI: 10.1038/s42003-025-08385-1
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