Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2.
Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2.
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DOI：
10.1016/j.neuron.2015.12.039
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发表时间：
2016-02-17
期刊：
影响因子：
16.2
通讯作者：
Giraldez AJ
中科院分区：
文献类型：
--
作者：
Hoffman EJ;Turner KJ;Fernandez JM;Cifuentes D;Ghosh M;Ijaz S;Jain RA;Kubo F;Bill BR;Baier H;Granato M;Barresi MJ;Wilson SW;Rihel J;State MW;Giraldez AJ
自闭症谱系障碍（ASD）是一组破坏性的神经发育综合征，影响高达1/68的儿童。尽管在ASD风险基因的识别方面取得了进展，但ASD的潜在机制仍然未知。Contactin Associated Protein-like 2（CNTNAP 2）中的纯合功能丧失突变与ASD密切相关。在这里，我们调查Cntnap 2的功能，并进行药理学筛选，以确定表型抑制。我们发现，斑马鱼cntnap 2突变体显示GABA能缺陷，特别是在前脑和药物诱导的癫痫发作的敏感性。高通量行为分析鉴定了cntnap 2突变体的夜间活动过度，而药理学测试揭示了GABA能和谷氨酸能系统的失调。最后，我们发现，雌激素受体激动剂引起的行为指纹反相关的cntnap 2突变体，并表明，植物雌激素鹰嘴豆素A特异性逆转突变的行为表型。这些结果确定雌激素化合物作为表型抑制剂，并阐明与自闭症相关的新的药理学途径。
Autism spectrum disorders (ASD) are a group of devastating neurodevelopmental syndromes that affect up to 1 in 68 children. Despite advances in the identification of ASD risk genes, the mechanisms underlying ASD remain unknown. Homozygous loss-of-function mutations in Contactin Associated Protein-like 2 (CNTNAP2) are strongly linked to ASD. Here we investigate the function of Cntnap2 and undertake pharmacological screens to identify phenotypic suppressors. We find that zebrafish cntnap2 mutants display GABAergic deficits particularly in the forebrain and sensitivity to drug-induced seizures. High-throughput behavioral profiling identifies nighttime hyperactivity in cntnap2 mutants, while pharmacological testing reveals dysregulation of GABAergic and glutamatergic systems. Finally, we find that estrogen receptor agonists elicit a behavioral fingerprint anti-correlative to that of cntnap2 mutants and show that the phytoestrogen biochanin A specifically reverses the mutant behavioral phenotype. These results identify estrogenic compounds as phenotypic suppressors and illuminate novel pharmacological pathways with relevance to autism.