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. 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.智力障碍影响全球1%至3%的人口，其遗传病因大多尚未明确。本研究以肌动蛋白细胞骨架调控因子CAPZA2为研究对象，通过构建CAPZA2杂合敲除（CAPZA2+/-）及CAPZA2杂合点突变（CAPZA2c.G776T/+）小鼠模型，探究其在神经发育障碍中的作用。 CAPZA2+/-与CAPZA2c.G776T/+小鼠的海马体及与学习记忆密切相关的前额叶皮层（prefrontal cortex, PFC）中，CAPZA2的表达水平均显著降低。值得注意的是，CAPZA2c.G776T/+小鼠体内CAPZA2的表达降幅不足50%。 行为学检测结果显示，CAPZA2+/-小鼠出现运动功能障碍、类焦虑行为，同时伴有空间记忆与非空间记忆损伤，以及社交互动缺陷。CAPZA2c.G776T/+小鼠也呈现出上述表型特征，从而验证了基因型与表型之间的相关性。 对这些基因编辑小鼠的形态学分析显示，其存在突触结构功能损伤，具体表现为海马体中树突棘密度升高、树突棘形态改变，以及前额叶皮层的树突复杂度降低。 对CAPZA2+/-小鼠海马组织的单细胞RNA测序（single-cell RNA-seq）分析显示，其存在广泛的转录失调现象，影响神经发育与突触功能相关基因的表达。突触后致密蛋白95（PSD95）与谷氨酸受体的水平异常，也佐证了上述结论。 上述研究结果凸显了该基因在大脑发育与功能维持中的核心作用，为理解并治疗神经发育障碍提供了潜在思路。本研究对野生型（wild-type, WT）与CAPZA2杂合敲除（CAPZA2+/-）小鼠的海马组织开展单细胞RNA测序，以对比两者的细胞群体比例。