Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities.
Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities.
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DOI：
10.1038/tp.2015.19
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发表时间：
2015-03-10
影响因子：
6.8
通讯作者：
Schwaller B
中科院分区：
文献类型：
--
作者：
Wöhr M;Orduz D;Gregory P;Moreno H;Khan U;Vörckel KJ;Wolfer DP;Welzl H;Gall D;Schiffmann SN;Schwaller B
基因突变和基因拷贝数变异与自闭症谱系障碍（ASD）有关。受影响的基因产物通常是涉及突触形成和/或功能的信号网络的一部分，导致兴奋/抑制（E/I）平衡的改变。尽管表达小清蛋白（PV）的中间神经元网络在ASD中获得了特别的关注，但对PV在ASD中的假定作用知之甚少。遗传小鼠模型代表了研究遗传和神经生物学因素在ASD中的作用的强大翻译工具。在这里，我们报告说，PV基因敲除小鼠（PV-/-）表现出与人类ASD患者存在的所有三种核心症状相关的行为表型：异常的互惠社交互动、沟通障碍以及重复和刻板的行为模式。PV耗竭小鼠还显示出ASD相关合并症的几种迹象，例如疼痛敏感性降低和惊吓反应，但癫痫发作易感性增加，而没有获得与焦虑，抑郁和精神分裂症相关的行为表型的证据。在以较低PV表达水平为特征的杂合子（PV+/−）小鼠中也观察到社交互动和交流减少，表明仅PV水平降低可能足以引起核心ASD样缺陷。PV-/-和PV+/-小鼠的结构磁共振成像测量进一步揭示了ASD相关的发育神经解剖学变化，包括短暂的皮质肥大和小脑发育不全。电生理学实验最终证明，在这些小鼠的E/I平衡被改变的抑制性和兴奋性突触传递的修改。在几个，主要是遗传的啮齿类动物模型的ASD的PV表达模式的变化的基础上，我们提出，在这些模型中下调PV可能代表的收敛点之一，从而提供了一个共同的联系，显然无关的ASD相关的突触结构/功能表型。
Gene mutations and gene copy number variants are associated with autism spectrum disorders (ASDs). Affected gene products are often part of signaling networks implicated in synapse formation and/or function leading to alterations in the excitation/inhibition (E/I) balance. Although the network of parvalbumin (PV)-expressing interneurons has gained particular attention in ASD, little is known on PV's putative role with respect to ASD. Genetic mouse models represent powerful translational tools for studying the role of genetic and neurobiological factors underlying ASD. Here, we report that PV knockout mice (PV−/−) display behavioral phenotypes with relevance to all three core symptoms present in human ASD patients: abnormal reciprocal social interactions, impairments in communication and repetitive and stereotyped patterns of behavior. PV-depleted mice also showed several signs of ASD-associated comorbidities, such as reduced pain sensitivity and startle responses yet increased seizure susceptibility, whereas no evidence for behavioral phenotypes with relevance to anxiety, depression and schizophrenia was obtained. Reduced social interactions and communication were also observed in heterozygous (PV+/−) mice characterized by lower PV expression levels, indicating that merely a decrease in PV levels might be sufficient to elicit core ASD-like deficits. Structural magnetic resonance imaging measurements in PV−/− and PV+/− mice further revealed ASD-associated developmental neuroanatomical changes, including transient cortical hypertrophy and cerebellar hypoplasia. Electrophysiological experiments finally demonstrated that the E/I balance in these mice is altered by modification of both inhibitory and excitatory synaptic transmission. On the basis of the reported changes in PV expression patterns in several, mostly genetic rodent models of ASD, we propose that in these models downregulation of PV might represent one of the points of convergence, thus providing a common link between apparently unrelated ASD-associated synapse structure/function phenotypes.
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影响因子：
4.9
作者：
Gogolla, Nadine;LeBlanc, Jocelyn J.;Quast, Kathleen B.;Sudhof, Thomas C.;Fagiolini, Michela;Hensch, Takao K.
通讯作者：
Hensch, Takao K.
聚类自闭症：在26个小鼠模型中使用神经解剖学差异来深入了解异质性。
影响因子：
11
作者：
Ellegood, J.;Anagnostou, E.;Babineau, B. A.;Crawley, J. N.;Lin, L.;Genestine, M.;DiCicco-Bloom, E.;Lai, J. K. Y.;Foster, J. A.;Penagarikano, O.;Geschwind, D. H.;Pacey, L. K.;Hampson, D. R.;Laliberte, C. L.;Mills, A. A.;Tam, E.;Osborne, L. R.;Kouser, M.;Espinosa-Becerra, F.;Xuan, Z.;Powell, C. M.;Raznahan, A.;Robins, D. M.;Nakai, N.;Nakatani, J.;Takumi, T.;van Eede, M. C.;Kerr, T. M.;Muller, C.;Blakely, R. D.;Veenstra-VanderWeele, J.;Henkelman, R. M.;Lerch, J. P.
通讯作者：
Lerch, J. P.
影响因子：
3.5
作者：
Kim, Yong-Sik;Harry, G. Jean;Kang, Hong Soon;Goulding, David;Wine, Rob N.;Kissling, Grace E.;Liao, Grace;Jetten, Anton M.
通讯作者：
Jetten, Anton M.
影响因子：
4.5
作者：
Ben-David E;Shifman S
通讯作者：
Shifman S
影响因子：
3.5
作者：
Madani, R;Kozlov, S;Wolfer, DP
通讯作者：
Wolfer, DP