Center for Neuroscience, University of California, Davis, CA 95618, USA.
Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16999-7004. doi: 10.1073/pnas.1006087107. Epub 2010 Sep 13.
Immune molecules have been discovered recently to play critical roles in the development, function, and plasticity of the cerebral cortex. MHC class I (MHCI) molecules are expressed in the central nervous system and regulate activity-dependent refinement of visual projections during late postnatal development. They have also been implicated in neurodevelopmental diseases such as schizophrenia and autism. Despite the excitement generated by these unique roles for immune proteins in the brain, little is known about how these molecules regulate cortical connections. The first step toward elucidating the mechanism is to identify the spatial and temporal distribution of MHCI proteins throughout development. Using a pan-specific antibody that recognizes many MHCI variants for biochemistry and immunohistochemistry, we found that MHCI proteins are expressed in the rat visual cortex at all ages examined-during the peak of synaptogenesis, the critical period of synaptic refinement, and adulthood. Their abundance in the cortex peaked during early postnatal development, declining during periods of plasticity and adulthood. In contrast to current assumptions, pre- and postembedding immunogold electron microscopy (EM) revealed that MHCI proteins were present both pre- and postsynaptically at all ages examined. They were often found in the postsynaptic density and were closely associated with synaptic vesicles in the presynaptic terminal. These results suggest a previously undescribed model in which MHCI molecules function on both sides of the synapse to regulate connectivity in the mammalian visual cortex before, during, and after the establishment of connections.
最近发现，免疫分子在大脑皮层的发育、功能和可塑性中发挥着关键作用。MHC Ⅰ类（MHCI）分子在中枢神经系统中表达，并调节出生后晚期视觉投射的活动依赖性细化。它们也与精神分裂症和自闭症等神经发育疾病有关。尽管这些免疫蛋白在大脑中的独特作用引起了人们的极大兴趣，但对于这些分子如何调节皮质连接知之甚少。阐明机制的第一步是确定 MHCI 蛋白在整个发育过程中的时空分布。我们使用一种针对多种 MHCI 变体的泛特异性抗体进行生物化学和免疫组织化学研究，发现 MHCI 蛋白在所有检查的年龄的大鼠视觉皮层中表达——在突触发生高峰期、突触细化的关键期和成年期。它们在皮质中的丰度在出生后早期达到峰值，在可塑性和成年期下降。与当前的假设相反，预包埋和包埋免疫金电子显微镜（EM）显示，在所有检查的年龄中，MHCI 蛋白都存在于突触前和突触后。它们经常出现在突触后密度中，并与突触前末端的突触小泡密切相关。这些结果表明了一种以前未描述的模型，其中 MHCI 分子在哺乳动物视觉皮层的连接建立之前、期间和之后都在突触的两侧发挥作用，以调节连接性。
