Department of Physiology, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.
Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):11074-9. doi: 10.1073/pnas.1005620107. Epub 2010 Jun 1.
Tuberous sclerosis (TSC) is an autosomally dominant neurocutaneous disease notable for its high comorbidity with autism in human patients. Studies of murine models of tuberous sclerosis have found defects in cognition and learning, but thus far have not uncovered deficits in social behaviors relevant to autism. To explore social communication and interaction in TSC2 heterozygous mice, we recorded ultrasonic vocalizations (USV) and found that although both wild-type (WT) and heterozygous pups born to WT dams showed similar call rates and patterns, baseline vocalization rates were elevated in pups born to heterozygous dams. Further analysis revealed several robust features of maternal potentiation in all but WT pups born to heterozygous dams. This lack of potentiation is suggestive of defects in mother-pup social interaction during or before the reunion period between WT pups and heterozygous dams. Intriguingly, male pups of both genotypes born to heterozygous dams showed particularly heightened call rates and burst patterns. Because our maternal retrieval experiments revealed that TSC2(+/-) dams exhibited improved defensive reactions against intruders and highly efficient pup retrieval performance, the alterations in their pups' USVs and maternal potentiation do not appear to result from poor maternal care. These findings suggest that a pup's interaction with its mother strongly influences the pup's vocal communication, revealing an intriguing dependence of this social behavior on TSC2 gene dosage of both parties involved. Our study of this murine model thus uncovers social abnormalities that arise from TSC haploinsufficiency and are suggestive of autism.
结节性硬化症（TSC）是一种常染色体显性神经皮肤疾病，其在人类患者中与自闭症的高共病率显著。对结节性硬化症的鼠模型研究发现了认知和学习方面的缺陷，但迄今为止尚未发现与自闭症相关的社交行为缺陷。为了探索 TSC2 杂合子小鼠的社会交流和互动，我们记录了超声波发声（USV），发现尽管来自 WT 母鼠的野生型（WT）和杂合子幼鼠的叫声率和模式相似，但来自杂合子母鼠的幼鼠的基线发声率升高。进一步的分析表明，除了来自杂合子母鼠的 WT 幼鼠外，所有幼鼠都表现出母体增强的几个稳健特征。这种缺乏增强作用表明，在 WT 幼鼠和杂合子母鼠的团聚期间或之前，存在母体-幼鼠社会互动的缺陷。有趣的是，来自杂合子母鼠的雄性幼鼠表现出特别高的叫声率和爆发模式。由于我们的母体检索实验表明，TSC2(+/-) 母鼠对入侵者表现出改善的防御反应和高效的幼鼠检索性能，因此它们幼鼠的 USV 和母体增强的变化似乎不是由于母性照顾不佳所致。这些发现表明，幼鼠与母亲的互动强烈影响幼鼠的声音交流，揭示了这种社会行为对双方 TSC2 基因剂量的强烈依赖。因此，我们对这种鼠模型的研究揭示了由 TSC 单倍不足引起的社会异常，这表明存在自闭症的可能性。
