Cadherin-8 is required for the first relay synapses to receive functional inputs from primary sensory afferents for cold sensation
Cadherin-8 is required for the first relay synapses to receive functional inputs from primary sensory afferents for cold sensation
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DOI：
10.1523/jneurosci.0243-07.2007
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发表时间：
2007-03-28
影响因子：
5.3
通讯作者：
Takeichi, Masatoshi
中科院分区：
文献类型：
--
作者：
Suzuki, Sachihiro C.;Furue, Hidemasa;Takeichi, Masatoshi
经典钙粘蛋白包括多种亚型，基于其亚型特异性结合性质介导选择性细胞-细胞粘附。大脑中的每一种亚型都是由功能性连接的核和板的有限群表达的。然而，是否每个亚型在神经回路中有任何特定的作用仍然很大程度上是未知的。在这里，我们发现钙粘蛋白-8 (cad8)，一种ii型经典钙粘蛋白，对冷感觉很重要，其回路是通过感觉神经元投射到脊髓中建立的。Cad8在脊髓背角（DH）的一部分神经元以及背根神经节（DRGs）的少数神经元中表达，大多数Cad8阳性的DRG神经元共表达低温/薄荷醇受体（TRPM8）。我们建立了cad8敲除小鼠，并使用杂合小鼠分析了目标cad8位点表达的lacZ标记。表达LacZ/cad8的感觉神经元和DH神经元连接在一起，cad8蛋白定位在它们之间形成的突触连接周围。然而，这种关系在cad8-/-小鼠中没有被破坏。我们对脊髓切片中的DH神经元进行了全细胞膜片钳记录，并结合薄荷醇刺激作为激发表达TRPM8的初级传入神经中枢末梢的工具。表达lacz的DH神经元表现为快速和慢速微型EPSCs。薄荷醇选择性地增加了cad8+/-切片中缓慢mEPSCs的频率，但这种作用在cad8-/-切片中被消除。cad8-/-小鼠也表现出对低温的敏感性降低。这些结果表明，cad8对于建立冷敏感感觉神经元与其靶DH神经元之间的生理偶联至关重要。
Classic cadherins, comprising multiple subtypes, mediate selective cell-cell adhesion based on their subtype-specific binding nature. Each subtype in the brain is expressed by restricted groups of functionally connected nuclei and laminas. However, whether each subtype has any specific role in neural circuitry remains largely unknown. Here, we show that cadherin-8 (cad8), a type-II classic cadherin, is important for cold sensation, whose circuitry is established by projection of sensory neurons into the spinal cord. Cad8 was expressed by a subset of neurons in the dorsal horn (DH) of the spinal cord, as well as by a small number of neurons in the dorsal root ganglia (DRGs), and the majority of cad8-positive DRG neurons coexpressed cold temperature/menthol receptor (TRPM8). We generated cad8 knock-out mice and analyzed lacZ markers expressed by the targeted cad8 locus using heterozygous mice. LacZ/cad8-expressing sensory neurons and DH neurons were connected together, and cad8 protein was localized around the synaptic junctions formed between them. This relation was, however, not disrupted in cad8-/-mice. We performed whole-cell patch-clamp recordings from DH neurons in spinal cord slices, in combination with menthol stimulation as a tool to excite central terminals of primary afferents expressing TRPM8. LacZ-expressing DH neurons exhibited fast and slow miniature EPSCs. Menthol selectively increased the frequency of the slow mEPSCs in cad8+/-slices, but this effect was abolished in cad8-/-slices. The cad8-/-mice also showed a reduced sensitivity to cold temperature. These results demonstrate that cad8 is essential for establishing the physiological coupling between cold-sensitive sensory neurons and their target DH neurons.