Neuronal major histocompatibility complex class I molecules are implicated in the generation of asymmetries in hippocampal circuitry
Neuronal major histocompatibility complex class I molecules are implicated in the generation of asymmetries in hippocampal circuitry
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DOI：
10.1113/jphysiol.2013.252122
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发表时间：
2013-10-01
影响因子：
5.5
通讯作者：
Ito, Isao
中科院分区：
文献类型：
--
作者：
Kawahara, Aiko;Kurauchi, Shotaro;Ito, Isao
关键点中心点大脑结构和功能中左右不对称的分子基础是一个中心问题neuroscience.center我们以前已经证明，由海马锥体神经元组成的神经元回路是不对称的，这取决于突触前输入的半球起源和突触后细胞的极性neurone.center在这项研究中，我们分析了缺乏主要组织相容性复合物I类（MHCI）稳定细胞表面表达的2-微球蛋白（2 m）缺陷小鼠的海马，MHCI在细胞中是重要immunity.center。我们发现2 m缺陷小鼠海马电路缺乏结构和功能不对称性，这表明MHCI对海马的产生至关重要asymmetry.center dot我们的研究结果提供了阐明产生大脑不对称性的细胞过程的第一步。摘要左右不对称是高阶脑功能的基本特征;然而，大脑不对称性的分子基础仍然不清楚。我们最近证明了海马回路的不对称性，这是由于锥体细胞突触中NMDA受体（NMDAR）亚单位GluR 2（NR 2B）的不对称分配造成的。2个亚基的这种不对称分配影响NMDAR的性质，并根据突触前输入的半球起源和突触后神经元的细胞极性产生两个突触群体，2-显性突触和2-非显性突触。为了确定产生不对称性的关键调节因子，我们分析了缺乏细胞表面表达主要组织相容性复合体I类（MHCI）的2-微球蛋白（2 m）缺陷小鼠的海马。尽管MHCI蛋白在免疫系统中是众所周知的，但越来越多的证据表明MHCI蛋白在脑中表达，并且是神经元连接的活性依赖性细化和正常突触可塑性所需的。我们发现2 m蛋白定位于野生型小鼠的海马突触中。在接受来自两个半球的输入的2 m缺陷海马突触中，NMDA EPSC对2亚单位选择性拮抗剂Ro 25-6981显示出与锥体神经元的顶侧和基底侧突触中的2显性突触相似的敏感性。除了刺激频率与突触可塑性之间的关系外，2 m缺失型突触的结构特征也与2-显性突触的结构特征相似。这些观察结果表明，2 m缺陷的海马缺乏2-非显性突触和回路不对称。我们的研究结果提供的证据支持MHCI分子在海马电路中产生不对称的关键作用。
Key points center dot The molecular basis of left-right asymmetries in brain structure and function is a central question in neuroscience.center dot We have previously demonstrated that the neuronal circuitry composed of hippocampal pyramidal neurones is asymmetrical depending on the hemispheric origin of presynaptic inputs and cell polarity of the postsynaptic neurone.center dot In this study, we analysed the hippocampus of 2-microglobulin (2m)-deficient mice lacking stable cell surface expression of major histocompatibility complex class I (MHCI), which is known to be important in cellular immunity.center dot We found that 2m-deficient mice lacked structural and functional asymmetries in hippocampal circuitry, suggesting that MHCI is critical for the generation of hippocampal asymmetry.center dot Our results provide a first step in elucidating the cellular process that generates brain asymmetries.Abstract Left-right asymmetry is a fundamental feature of higher-order brain function; however, the molecular basis of brain asymmetry has remained unclear. We have recently demonstrated asymmetries in hippocampal circuitry resulting from the asymmetrical allocation of NMDA receptor (NMDAR) subunit GluR2 (NR2B) in pyramidal cell synapses. This asymmetrical allocation of 2 subunits affects the properties of NMDARs and generates two populations of synapses, 2-dominant' and 2-non-dominant' synapses, according to the hemispheric origin of presynaptic inputs and cell polarity of the postsynaptic neurone. To identify key regulators for generating asymmetries, we analysed the hippocampus of 2-microglobulin (2m)-deficient mice lacking cell surface expression of major histocompatibility complex class I (MHCI). Although MHCI proteins are well known in the immune system, accumulating evidence indicates that MHCI proteins are expressed in the brain and are required for activity-dependent refinement of neuronal connections and normal synaptic plasticity. We found that 2m proteins were localised in hippocampal synapses in wild-type mice. NMDA EPSCs in 2m-deficient hippocampal synapses receiving inputs from both hemispheres showed similar sensitivity to Ro 25-6981, an 2 subunit-selective antagonist, with those in 2-dominant' synapses for both the apical and basal synapses of pyramidal neurones. The structural features of the 2m-deficient synapse in addition to the relationship between the stimulation frequency and synaptic plasticity were also comparable to those of 2-dominant' synapses. These observations indicate that the 2m-deficient hippocampus lacks 2-non-dominant' synapses and circuit asymmetries. Our findings provide evidence supporting a critical role of MHCI molecules for generating asymmetries in hippocampal circuitry.