Child Study Center, Yale University, 230 South Frontage Rd, New Haven, CT 06520, United States; Department of Pharmacology, Yale University, 333 Cedar Street, New Haven, CT 06520, United States.
Child Study Center, Yale University, 230 South Frontage Rd, New Haven, CT 06520, United States.
Behav Brain Res. 2020 Aug 5;391:112713. doi: 10.1016/j.bbr.2020.112713. Epub 2020 May 24.
Autism spectrum disorders (ASDs) are highly prevalent childhood illnesses characterized by impairments in communication, social behavior, and repetitive behaviors. Studies have found aberrant synaptic plasticity and neuronal connectivity during the early stages of brain development and have suggested that these contribute to an increased risk for ASD. STEP is a protein tyrosine phosphatase that regulates synaptic plasticity and is implicated in several cognitive disorders. Here we test the hypothesis that STEP may contribute to some of the aberrant behaviors present in the VPA-induced mouse model of ASD. In utero VPA exposure of pregnant dams results in autistic-like behavior in the pups, which is associated with a significant increase in the STEP expression in the prefrontal cortex. The elevated STEP protein levels are correlated with increased dephosphorylation of STEP substrates GluN2B, Pyk2 and ERK, suggesting upregulated STEP activity. Moreover, pharmacological inhibition of STEP rescues the sociability, repetitive and abnormal anxiety phenotypes commonly associated with ASD. These data suggest that STEP may play a role in the VPA model of ASD and STEP inhibition may have a potential therapeutic benefit in this model.
自闭症谱系障碍（ASD）是一种常见的儿童疾病，其特征是在沟通、社交行为和重复行为方面存在障碍。研究发现，在大脑发育的早期阶段存在异常的突触可塑性和神经元连接，这表明它们增加了患 ASD 的风险。STEP 是一种蛋白酪氨酸磷酸酶，可调节突触可塑性，与几种认知障碍有关。在这里，我们检验了一个假设，即 STEP 可能导致 VPA 诱导的 ASD 小鼠模型中存在的一些异常行为。对妊娠母体进行 VPA 暴露会导致幼崽出现类似自闭症的行为，这与前额叶皮层中 STEP 表达的显著增加有关。升高的 STEP 蛋白水平与 STEP 底物 GluN2B、Pyk2 和 ERK 的去磷酸化增加相关，表明 STEP 活性上调。此外，STE 抑制的药理学抑制可挽救通常与 ASD 相关的社交、重复和异常焦虑表型。这些数据表明，STEP 可能在 VPA 诱导的 ASD 模型中发挥作用，STE 抑制在该模型中可能具有潜在的治疗益处。
