Center for Neuroscience, University of California, Davis, CA 95618, USA.
J Neurosci. 2013 Aug 21;33(34):13791-804. doi: 10.1523/JNEUROSCI.2366-13.2013.
Major histocompatibility complex class I (MHCI) molecules negatively regulate cortical connections and are implicated in neurodevelopmental disorders, including autism spectrum disorders and schizophrenia. However, the mechanisms that mediate these effects are unknown. Here, we report a novel MHCI signaling pathway that requires the myocyte enhancer factor 2 (MEF2) transcription factors. In young rat cortical neurons, MHCI regulates MEF2 in an activity-dependent manner and requires calcineurin-mediated activation of MEF2 to limit synapse density. Manipulating MEF2 alone alters synaptic strength and GluA1 content, but not synapse density, implicating activity-dependent MEF2 activation as critical for MHCI signaling. The MHCI-MEF2 pathway identified here also mediates the effects of a mouse model of maternal immune activation (MIA) on connectivity in offspring. MHCI and MEF2 levels are higher, and synapse density is lower, on neurons from MIA offspring. Most important, dysregulation of MHCI and MEF2 is required for the MIA-induced reduction in neural connectivity. These results identify a previously unknown MHCI-calcineurin-MEF2 signaling pathway that regulates the establishment of cortical connections and mediates synaptic defects caused by MIA, a risk factor for autism spectrum disorders and schizophrenia.
主要组织相容性复合体 I 类 (MHC I) 分子负向调节皮质连接，并与神经发育障碍有关，包括自闭症谱系障碍和精神分裂症。然而，介导这些效应的机制尚不清楚。在这里，我们报告了一种新的 MHC I 信号通路，该通路需要肌细胞增强因子 2 (MEF2) 转录因子。在年轻大鼠皮质神经元中，MHC I 以活性依赖的方式调节 MEF2，并且需要钙调神经磷酸酶介导的 MEF2 激活来限制突触密度。单独操纵 MEF2 会改变突触强度和 GluA1 含量，但不会改变突触密度，这表明活性依赖性 MEF2 激活对 MHC I 信号至关重要。在这里鉴定的 MHC I-MEF2 通路也介导了母体免疫激活 (MIA) 对后代连接的影响。MIA 后代神经元上的 MHC I 和 MEF2 水平更高，突触密度更低。最重要的是，MIA 诱导的神经连接减少需要 MHC I 和 MEF2 的失调。这些结果确定了一种以前未知的 MHC I-钙调神经磷酸酶-MEF2 信号通路，该通路调节皮质连接的建立，并介导由 MIA 引起的突触缺陷，MIA 是自闭症谱系障碍和精神分裂症的一个风险因素。
