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

Intellectual disability affects 1%-3% of the global population, with many unidentified genetic causes. This study investigates the role of CAPZA2, an actin cytoskeleton regulator, in neurodevelopmental disorders using CAPZA2 heterozygous knockout (CAPZA2+/-) and heterozygous point mutant (CAPZA2c.G776T/+) mice. CAPZA2+/- and CAPZA2c.G776T/+ mice demonstrated notable decreases in CAPZA2 expression within the hippocampus and prefrontal cortex (PFC), crucial for learning and memory. Interestingly, the reduction of CAPZA2 in CAPZA2c.G776T/+ mice is less than 50%. Behavioral assays revealed that CAPZA2+/- mice exhibited motor dysfunction and anxiety-like behaviors, along with impairments in both spatial and non-spatial memory, accompanied by deficits in social interactions. These phenotypic manifestations were also mirrored in the CAPZA2c.G776T/+ mice, thus validating the genotype-phenotype correlation. Morphological analyses of these gene-edited mice indicated structural synaptic impairments, with increased dendritic spine density, altered spine morphology in the hippocampus, and decreased dendritic complexity in the PFC. Single-cell RNA-seq analysis of hippocampal tissue in CAPZA2+/- mice showed widespread transcriptional dysregulation, affecting neurodevelopment and synaptic function genes. The altered PSD95 and glutamate receptor levels support these findings. These in-sights highlight the gene's essential role in brain development and function, with po-tential implications for understanding and treating neurodevelopmental disorders. Overall design: This study performed single-cell RNA sequencing on hippocampal tissues from wild-type (WT) and CAPZA2 heterozygous knockout (CAPZA2+/-) mice to compare cell population proportions.