IL-17a promotes sociability in mouse models of neurodevelopmental disorders.
IL-17a promotes sociability in mouse models of neurodevelopmental disorders.
复制标题
DOI：
10.1038/s41586-019-1843-6
复制
发表时间：
2020-01
期刊：
影响因子：
64.8
通讯作者：
Choi GB
中科院分区：
文献类型：
--
作者：
Reed MD;Yim YS;Wimmer RD;Kim H;Ryu C;Welch GM;Andina M;King HO;Waisman A;Halassa MM;Huh JR;Choi GB
一部分患有自闭症谱系障碍的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。在这里，我们阐明了炎症对小鼠社会行为缺陷有益影响的分子和神经机制。我们比较了小鼠在胚胎发生期间暴露于母体免疫激活（MIA）的神经发育障碍环境模型，以及接触相关蛋白样2 （Cntnap2）、脆性X智力迟钝-1 （Fmr1）或Sh3和多锚蛋白重复结构域3 （Shank3）基因缺陷的小鼠模型。我们确定，暴露于MIA的后代的社会行为缺陷可以通过脂多糖（LPS）引起的炎症反应暂时得到拯救。这种行为拯救伴随着初级体感觉皮层异常颗粒区（S1DZ）神经元活动的减少，该区域的过度活动先前与暴露于MIA的后代相关的行为表型的表现有关。相比之下，在单基因模型中，我们没有观察到lps诱导的社会赤字的拯救。我们证明，MIA和单基因模型之间对LPS处理的反应性差异源于细胞因子产生水平的差异。在单基因突变小鼠中，LPS处理诱导的白细胞介素-17a （IL-17a）的数量与MIA后代所诱导的数量没有可比性；通过直接将IL-17a传递到S1DZ中来绕过这种差异，足以促进单基因突变小鼠和MIA后代的社交能力。相反，在S1DZ神经元中去除IL-17受体亚基a （IL-17Ra）的表达会消除LPS逆转MIA后代社交表型的能力。我们的数据支持一种神经免疫机制，该机制是神经发育障碍的基础，其中炎症期间IL-17a的产生可以通过直接影响中枢神经系统的神经元活动来改善社会行为缺陷的表达。
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,. 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,with mouse models that are genetically deficient for contactin-associated protein-like 2 (Cntnap2), fragile X mental retardation-1 (Fmr1) or Sh3 and multiple ankyrin repeat domains 3 (Shank3). 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. 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.
登录
查看更多内容
影响因子：
20.8
作者：
Lyall K;Croen L;Daniels J;Fallin MD;Ladd-Acosta C;Lee BK;Park BY;Snyder NW;Schendel D;Volk H;Windham GC;Newschaffer C
通讯作者：
Newschaffer C
影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
DOI：
10.1073/pnas.0700293104
发表时间：
2007-03-20
影响因子：
11.1
作者：
Armbruster, Blaine N.;Li, Xiang;Roth, Bryan L.
通讯作者：
Roth, Bryan L.
影响因子：
64.8
作者：
Kim S;Kim H;Yim YS;Ha S;Atarashi K;Tan TG;Longman RS;Honda K;Littman DR;Choi GB;Huh JR
通讯作者：
Huh JR
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.