Loss of Tsc2 in Purkinje cells is associated with autistic-like behavior in a mouse model of tuberous sclerosis complex
Loss of Tsc2 in Purkinje cells is associated with autistic-like behavior in a mouse model of tuberous sclerosis complex
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DOI：
10.1016/j.nbd.2012.10.014
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发表时间：
2013-03-01
影响因子：
6.1
通讯作者：
Gambello, Michael J.
中科院分区：
文献类型：
--
作者：
Reith, R. Michelle;McKenna, James;Gambello, Michael J.
结节性硬化症（TSC）是一种显性肿瘤抑制疾病，由TSC1或TSC2突变引起。TSC引起严重的神经病理学，通常导致高达60%的患者出现自闭症谱系障碍（asd）。这两种疾病之间的解剖学和神经生理学联系尚不清楚。我们已经建立并表征了一种具有浦肯野细胞特异性Tsc2缺失的新型TSC小鼠模型。这些Tsc2f / -;Cre小鼠表现进行性浦肯野细胞变性。由于Purkinje细胞的丢失是ASD患者死后发现的一个很好的报道，我们进行了一系列行为测试来评估Tsc2f/-；Cre小鼠表现出自闭症样缺陷。Tsc2f / -;通过弹珠掩埋活动评估，Cre小鼠的重复行为增加。利用三室仪器对社会行为进行评估，我们发现Tsc2f/-；Cre小鼠表现出行为缺陷，在陌生的老鼠和无生命的物体之间，或者在新奇的老鼠和熟悉的老鼠之间，没有表现出偏好。我们还发现了Tsc2f/f的社会缺陷；这表明浦肯野细胞病理足以诱导asd样行为。重要的是，社会行为缺陷可以通过雷帕霉素治疗来预防。总之，这些结果表明，在Tsc2单倍不足的背景下，浦肯野细胞中Tsc2的缺失会导致自闭症样的行为缺陷。这些研究提供了令人信服的证据，证明浦肯野细胞丢失和/或功能障碍可能是TSC和ASD之间的重要联系，也是导致ASD表型的一般解剖现象。(C) 2012爱思唯尔公司版权所有。
Tuberous sclerosis complex (TSC) is a dominant tumor suppressor disorder caused by mutations in either TSC1 or TSC2. TSC causes substantial neuropathology, often leading to autism spectrum disorders (ASDs) in up to 60% of patients. The anatomic and neurophysiologic links between these two disorders are not well understood. We have generated and characterized a novel TSC mouse model with Purkinje cell specific Tsc2 loss. These Tsc2f/-;Cre mice exhibit progressive Purkinje cell degeneration. Since loss of Purkinje cells is a well reported postmortem finding in patients with ASD, we conducted a series of behavior tests to asses if Tsc2f/-;Cre mice displayed autistic-like deficits. Tsc2f/-;Cre mice demonstrated increased repetitive behavior as assessed with marble burying activity. Using the three chambered apparatus to asses social behavior, we found that Tsc2f/-;Cre mice showed behavioral deficits, exhibiting no preference between a stranger mouse and an inanimate object, or between a novel and a familiar mouse. We also detected social deficits in Tsc2f/f;Cre mice, suggesting that Purkinje cell pathology is sufficient to induce ASD-like behavior. Importantly, social behavior deficits were prevented with rapamycin treatment. Altogether, these results demonstrate that loss of Tsc2 in Purkinje cells in a Tsc2-haploinsufficient background leads to autistic-like behavioral deficits. These studies provide compelling evidence that Purkinje cell loss and/or dysfunction may be an important link between TSC and ASD as well as a general anatomic phenomenon that contributes to the ASD phenotype. (C) 2012 Elsevier Inc. All rights reserved.