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IL-17a promotes sociability in mouse models of neurodevelopmental disorders

机译：IL-17a促进神经发育障碍小鼠模型的社交能力

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摘要

A subset of children with autism spectrum disorder appear to show an improvement in their behavioural symptoms during the course of a fever, a sign of systemic inflammation(1,2.) Here we elucidate the molecular and neural mechanisms that underlie the beneficial effects of inflammation on social behaviour deficits in mice. We compared an environmental model of neurodevelopmental disorders in which mice were exposed to maternal immune activation (MIA) during embryogenesis(3,4) with mouse models that are genetically deficient for contactin-associated protein-like 2 (Cntnap2)5, fragile X mental retardation-1 (Fmr1)(6) or Sh3 and multiple ankyrin repeat domains 3 (Shank3)(7). We establish that the social behaviour deficits in offspring exposed to MIA can be temporarily rescued by the inflammatory response elicited by the administration of lipopolysaccharide (LPS). This behavioural rescue was accompanied by a reduction in neuronal activity in the primary somatosensory cortex dysgranular zone (S1DZ), the hyperactivity of which was previously implicated in the manifestation of behavioural phenotypes associated with offspring exposed to MIA(8.) By contrast, we did not observe an LPS-induced rescue of social deficits in the monogenic models. We demonstrate that the differences in responsiveness to the LPS treatment between the MIA and the monogenic models emerge from differences in the levels of cytokine production. LPS treatment in monogenic mutant mice did not induce amounts of interleukin-17a (IL-17a) comparable to those induced in MIA offspring; bypassing this difference by directly delivering IL-17a into S1DZ was sufficient to promote sociability in monogenic mutant mice as well as in MIA offspring. Conversely, abrogating the expression of IL-17 receptor subunit a (IL-17Ra) in the neurons of the S1DZ eliminated the ability of LPS to reverse the sociability phenotypes in MIA offspring. Our data support a neuroimmune mechanism that underlies neurodevelopmental disorders in which the production of IL-17a during inflammation can ameliorate the expression of social behaviour deficits by directly affecting neuronal activity in the central nervous system.
机译：自闭症谱系障碍的一部分儿童在发烧过程中表现出行为症状的改善，这是全身性炎症的迹象（1,2。）在这里，我们阐明了炎症有益作用的分子和神经机制对小鼠的社会行为缺陷。我们比较了一种神经发育障碍的环境模型，其中小鼠在胚胎发生过程中暴露于母体免疫激活（MIA）（3,4）与遗传上缺乏接触素相关蛋白样2（Cntnap2）5，脆弱的X智力的小鼠模型。延迟1（Fmr1）（6）或Sh3和多个锚蛋白重复域3（Shank3）（7）。我们建立了暴露于MIA的后代的社交行为缺陷可以通过脂多糖（LPS）引起的炎症反应来暂时挽救。这种行为抢救伴随着初级体感皮层运动障碍区（S1DZ）神经元活动的减少，该活动过度与先前暴露于MIA的后代相关的行为表型的表现有关（8.）。相比之下，我们做了在单基因模型中未观察到LPS引起的对社会缺陷的救助。我们证明，MIA和单基因模型之间对LPS治疗的反应性差异来自细胞因子产生水平的差异。在单基因突变小鼠中进行LPS处理，其诱导的白细胞介素17a（IL-17a）的量与MIA后代中诱导的相当。通过直接将IL-17a传递到S1DZ中来绕过这种差异足以在单基因突变小鼠以及MIA后代中提高社交能力。相反，废除S1DZ神经元中IL-17受体亚基a（IL-17Ra）的表达消除了LPS逆转MIA后代社会型表型的能力。我们的数据支持了神经发育障碍的神经免疫机制，其中炎症过程中IL-17a的产生可通过直接影响中枢神经系统的神经元活动来改善社交行为缺陷的表达。

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  • 来源
    《Nature》 |2020年第7789期|249-253|共5页
  • 作者

    Reed Michael Douglas; Yim Yeong Shin; Wimmer Ralf D.; Kim Hyunju; Ryu Changhyeon; Welch Gwyneth Margaret; Andina Matias; King Hunter Oren; Waisman Ari; Halassa Michael M.; Huh Jun R.; Choi Gloria B.;

  • 作者单位

    MIT Picower Inst Learning & Memory 77 Massachusetts Ave Cambridge MA 02139 USA|MIT Dept Brain & Cognit Sci 77 Massachusetts Ave Cambridge MA 02139 USA;

    MIT Picower Inst Learning & Memory 77 Massachusetts Ave Cambridge MA 02139 USA|MIT Dept Brain & Cognit Sci 77 Massachusetts Ave Cambridge MA 02139 USA|MIT McGovern Inst Brain Res 77 Massachusetts Ave Cambridge MA 02139 USA;

    MIT Dept Brain & Cognit Sci 77 Massachusetts Ave Cambridge MA 02139 USA;

    Johannes Gutenberg Univ Mainz Univ Med Ctr Inst Mol Med Mainz Germany;

    Harvard Med Sch Blavatnik Inst Dept Immunol Boston MA 02115 USA|Harvard Med Sch Evergrande Ctr Immunol Dis Boston MA 02115 USA|Brigham & Womens Hosp 75 Francis St Boston MA 02115 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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