小柯机器人

美国麻省理工学院Gloria B. Choi和美国哈佛医学院布拉瓦特尼克研究所Jun R. Huh课题组合作发现，IL-17a促进神经发育障碍模型小鼠的社交能力。该研究于2019年12月18日在线发表在《自然》杂志上。

他们阐明了炎症对小鼠社交行为缺陷的有益影响的分子和神经机制。他们比较了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）与遗传上缺乏接触素相关蛋白样2（Cntnap2）、脆弱的X智力低下-1的小鼠模型（Fmr1）或Sh3和多个锚蛋白重复结构域3（Shank3）。

他们建立了暴露于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。这种行为挽救伴随着初级体感皮层运动区（S1DZ）神经元活动的减少，其活动过度先前与暴露于MIA8的后代相关的行为表型的表现有关。相比之下，他们没有在单基因模型中观察到LPS诱导的社会缺陷的挽救。

他们证明，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。

他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。

据介绍，有一部分自闭症谱系障碍儿童在发烧时现出行为症状的改善，这是全身性炎症的迹象。

附：英文原文

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

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

Issue&Volume: 2019-12-18

Abstract: 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 inflammation1,2. 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 embryogenesis3,4 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 MIA8. 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. IL-17a induced by immune activation affects cortical neural activity and promotes social interaction in a mouse model of neurodevelopmental disorders.

DOI: 10.1038/s41586-019-1843-6

Source:

https://www.nature.com/articles/s41586-019-1843-6

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