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 (CAPZA2^c.G776T/+) mice. CAPZA2^+/- and CAPZA2^c.G776T/+ mice demonstrate notable decreases in CAPZA2 expression within the hippocampus and prefrontal cortex (PFC), crucial for learning and memory. Interestingly, the reduction of CAPZA2 in CAPZA2^c.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 are also mirrored in the CAPZA2^c.G776T/+ mice, thus validating the genotype-phenotype correlation. Morphological analyses of these gene-edited mice indicate 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 shows widespread transcriptional dysregulation, affecting neurodevelopment and synaptic function genes. The altered PSD95 and glutamate receptor levels support these findings. These insights highlight the gene's essential role in brain development and function, with potential implications for understanding and treating neurodevelopmental disorders.