Transcriptome analysis of Adnp-heterozygous mice in the hippocampus

ADNP syndrome, involving the ADNP transcription factor in the SWI/SNF chromatin-remodeling complex, is characterized by developmental delay, intellectual disability, and autism spectrum disorders (ASD). In ASD, ADNP is a highly penetrant risk gene, accounting for ~0.17% cases. Although Adnp-haploinsufficient mice display various phenotypic deficits, the underlying synaptic mechanisms are poorly understood. Here we report age-differential synaptic plasticity deficits associated with cognitive inflexibility and CaMKIIalpha hyperactivity in Adnp-mutant mice. These mice show impaired and inflexible contextual learning and memory additional to social and anxiety-related deficits in adults long after a marked decrease in ADNP protein levels to ~10% of newborn levels in juveniles. In addition, Adnp-mutant adults show abnormally enhanced long-term potentiation in adults but not in juveniles. This accompanies CaMKIIalpha hyperactivity involving increased baseline autophosphorylation, as revealed by unbiased proteomic analyses. Therefore, ADNP haploinsufficiency in mice leads to cognitive inflexibility involving altered synaptic plasticity and signaling in adults long after a marked decrease in Adnp expression in juveniles. Transcriptome analysis of Adnp-heterozygous mice in the hippocampus of adults and juveniles.ADNP综合征涉及SWI/SNF染色质重塑复合物中的ADNP转录因子，以发育迟缓、智力障碍及自闭症谱系障碍（ASD）为核心临床表型。在自闭症谱系障碍病例中，ADNP是一种高外显率风险基因，约占总病例的0.17%。尽管Adnp单倍剂量不足小鼠可表现出多种表型缺陷，但其潜在的突触机制仍尚不明确。本研究报道了Adnp突变小鼠中与认知僵化及CaMKIIalpha过度激活相关的年龄差异性突触可塑性缺陷。在幼年阶段，ADNP蛋白水平已显著降至新生小鼠的约10%；成年后，该类小鼠除出现社交与焦虑相关行为缺陷外，还存在受损且僵化的情境学习与记忆能力。此外，Adnp突变成年小鼠呈现异常增强的长时程增强效应，而幼年小鼠则未观察到此现象。通过无偏蛋白质组学分析，研究发现该现象伴随CaMKIIalpha过度激活，具体表现为基础自磷酸化水平升高。综上，在幼年阶段Adnp表达显著下降后，小鼠的ADNP单倍剂量不足会导致成年个体出现认知僵化，该过程涉及突触可塑性及信号通路的异常改变。本研究同时对成年与幼年小鼠海马体中的Adnp杂合子小鼠开展了转录组分析。