Wei Hongen, Ma Yuehong, Liu Jianrong, Ding Caiyun, Jin Guorong, Wang Yi, Hu Fengyun, Yu Li
Department of Rehabilitation Medicine, Shanxi Provincial People's Hospital, Affiliate of Shanxi Medical University, Taiyuan, China.
Central Laboratory, Shanxi Provincial People's Hospital, Affiliate of Shanxi Medical University, Taiyuan, China.
Biochim Biophys Acta. 2016 Oct;1862(10):1918-25. doi: 10.1016/j.bbadis.2016.07.013. Epub 2016 Jul 25.
Autism is a severe neurodevelopmental disorder with a large population prevalence, characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. The BTBR T(+)Itpr3(tf) (BTBR) mice have emerged as strong candidates to serve as models of a range of autism-relevant behaviors. Increasing evidences suggest that interleukin (IL)-6, one of the most important neuroimmune factors, was involved in the pathophysiology of autism. It is of great importance to further investigate whether therapeutic interventions in autism can be achieved through the manipulation of IL-6. Our previous studies showed that IL-6 elevation in the brain could mediate autistic-like behaviors, possibly through the imbalances of neural circuitry and impairments of synaptic plasticity. In this study, we evaluate whether inhibiting IL-6 signaling in the brain is sufficient to modulate the autism-like behaviors on the BTBR mice. The results showed that chronic infusion of an analog of the endogenous IL-6 trans-signaling blocker sgp130Fc protein increased the sociability in BTBR mice. Furthermore, no change was observed in the number of excitatory synapse, level of synaptic proteins, density of dentitic spine and postsynaptic density in BTBR cortices after inhibiting IL-6 trans-signaling. However, inhibition of IL-6 trans-signaling increased the evoked glutamate release in synaptoneurosomes from the cerebral cortex of BTBR mice. Our findings suggest that inhibition of excessive production of IL-6 may have selective therapeutic efficacy in treating abnormal social behaviors in autism.
自闭症是一种严重的神经发育障碍，在人群中患病率较高，其特征为社交互动异常、沟通缺陷以及兴趣受限的重复行为。BTBR T(+)Itpr3(tf)（BTBR）小鼠已成为一系列与自闭症相关行为模型的有力候选者。越来越多的证据表明，白细胞介素（IL）-6作为最重要的神经免疫因子之一，参与了自闭症的病理生理过程。进一步研究是否可以通过调控IL-6来实现自闭症的治疗干预具有重要意义。我们之前的研究表明，大脑中IL-6水平升高可能通过神经回路失衡和突触可塑性受损介导类似自闭症的行为。在本研究中，我们评估抑制大脑中的IL-6信号是否足以调节BTBR小鼠的自闭症样行为。结果显示，长期输注内源性IL-6转信号阻断剂sgp130Fc蛋白的类似物可增加BTBR小鼠的社交能力。此外，抑制IL-6转信号后，BTBR皮质中兴奋性突触数量、突触蛋白水平、树突棘密度和突触后密度均未观察到变化。然而，抑制IL-6转信号可增加BTBR小鼠大脑皮质突触体中诱发的谷氨酸释放。我们的研究结果表明，抑制IL-6的过量产生可能对治疗自闭症的异常社交行为具有选择性治疗效果。
