Excessive beta-catenin in excitatory neurons results in reduced social and increased repetitive behaviors and altered expression of multiple genes linked to human autism

Multiple human autism risk genes are predicted to converge on the beta-catenin (beta-cat)/Wnt pathway. However, direct tests to link beta-cat up- or down-regulation with autism are largely lacking, and the associated pathophysiological changes are poorly defined. Here we identify excessive beta-cat as a risk factor that causes expression changes in several genes relevant to human autism. Our studies utilize mouse lines with beta-cat dysregulation in forebrain excitatory neurons, identified as cell types with convergent expression of autism-linked genes in both human and mouse brains. We show that mice expressing excessive beta-cat display behavioral and molecular changes, including decreased social interest, increased repetitive behaviors, reduced parvalbumin and altered expression levels of additional genes identified as potential risk factors for human autism. These behavioral and molecular phenotypes are averted by reducing beta-cat in neurons predisposed by gene mutations to express elevated beta-cat. Using next-generation sequencing of the prefrontal cortex, we identify dysregulated genes that are shared between mouse lines with excessive beta-cat and autism-like behaviors, but not mouse lines with reduced beta-cat and normal social behavior. Our findings provide critical new insights into beta-cat, Wnt pathway dysregulation in the brain causing behavioral phenotypes relevant to the disease and the molecular etiology which includes several human autism risk genes. Examination of gene changes in the prefrontal cortex of different mouse models with excessive or reduced beta-catenin levels多项研究预测，多种人类自闭症风险基因可汇聚至β-连环蛋白（beta-catenin, β-cat）/Wnt信号通路。然而，目前尚缺乏直接验证β-cat上调或下调与自闭症之间关联的实验研究，相关病理生理改变也尚未被清晰阐明。本研究鉴定出过量表达的β-cat可作为风险因子，引发多种与人类自闭症相关的基因表达异常。本研究采用在前脑兴奋性神经元中存在β-cat失调的小鼠模型，这类神经元被证实是人类与小鼠大脑中自闭症关联基因汇聚表达的细胞类型。研究结果显示，过量表达β-cat的小鼠会出现行为与分子层面的异常，包括社交兴趣减退、重复行为增多、小白蛋白（parvalbumin）表达水平降低，以及其他被鉴定为人类自闭症潜在风险因子的基因表达谱改变。若在因基因突变而本会过量表达β-cat的神经元中下调β-cat水平，则可规避上述行为与分子表型。通过对前额叶皮层（prefrontal cortex）开展下一代测序（next-generation sequencing），我们鉴定出在过量表达β-cat且表现类自闭症行为的小鼠模型中存在失调的共享基因，而在β-cat水平降低且社交行为正常的小鼠模型中则未检测到此类失调基因。本研究的发现为大脑中β-cat/Wnt通路失调引发与自闭症相关的行为表型，以及包含多种人类自闭症风险基因的分子病因学机制提供了关键的全新认知。针对β-连环蛋白水平过高或过低的不同小鼠模型的前额叶皮层基因表达变化的研究