Autism Spectrum Disorders (ASD) patients experience disturbed nociception in the form of either hyposensitivity to pain or allodynia. A substantial amount of processing of somatosensory and nociceptive stimulus takes place in the dorsal spinal cord. However, many of these circuits are not very well understood in the context of nociceptive processing in ASD. We have used a Shank2−/− mouse model, which displays a set of phenotypes reminiscent of ASD, and performed behavioural and microscopic analysis to investigate the role of dorsal horn circuitry in nociceptive processing of ASD. We determined that Shank2−/− mice display increased sensitivity to formalin pain and thermal preference, but a sensory specific mechanical allodynia. We demonstrate that high levels of Shank2 expression identifies a subpopulation of neurons in murine and human dorsal spinal cord, composed mainly by glycinergic interneurons and that loss of Shank2 causes the decrease in NMDAR in excitatory synapses on these inhibitory interneurons. In fact, in the subacute phase of the formalin test, glycinergic interneurons are strongly activated in wild type (WT) mice but not in Shank2−/− mice. Consequently, nociception projection neurons in laminae I are activated in larger numbers in Shank2−/− mice. Our investigation is limited to male mice, in agreement with the higher representation of ASD in males; therefore, caution should be applied to extrapolate the findings to females. Furthermore, ASD is characterized by extensive genetic diversity and therefore the findings related to Shank2 mutant mice may not necessarily apply to patients with different gene mutations. Since nociceptive phenotypes in ASD range between hyper- and hypo-sensitivity, diverse mutations may affect the circuit in opposite ways. Our findings prove that Shank2 expression identifies a new subset of inhibitory interneurons involved in reducing the transmission of nociceptive stimuli and whose unchecked activation is associated with pain hypersensitivity. We provide evidence that dysfunction in spinal cord pain processing may contribute to the nociceptive phenotypes in ASD.

中文翻译：

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Shank2 识别出参与自闭症模型伤害感受改变的甘氨酸神经元子集

自闭症谱系障碍 (ASD) 患者会经历伤害感受障碍，表现为对疼痛不敏感或异常性疼痛。大量的体感和伤害性刺激的处理发生在背侧脊髓。然而，在自闭症谱系障碍（ASD）伤害性感受处理的背景下，许多这些回路并没有得到很好的理解。我们使用了 Shank2−/− 小鼠模型，该模型显示了一组让人想起 ASD 的表型，并进行了行为和微观分析，以研究背角电路在 ASD 伤害性处理中的作用。我们确定 Shank2−/− 小鼠对福尔马林疼痛和热偏好的敏感性增加，但有感觉特异性机械异常性疼痛。我们证明，高水平的 Shank2 表达识别了小鼠和人类背脊髓中的神经元亚群，主要由甘氨酸能中间神经元组成，并且 Shank2 的缺失导致这些抑制性中间神经元上的兴奋性突触中 NMDAR 的减少。事实上，在福尔马林试验的亚急性阶段，甘氨酸能中间神经元在野生型（WT）小鼠中被强烈激活，但在 Shank2−/− 小鼠中则不然。因此，在 Shank2−/− 小鼠中，I 层中的伤害感受投射神经元被大量激活。我们的研究仅限于雄性小鼠，这与雄性小鼠中自闭症谱系障碍（ASD）的较高代表性相一致；因此，将研究结果外推到女性时应谨慎。此外，ASD 的特点是广泛的遗传多样性，因此与 Shank2 突变小鼠相关的发现可能不一定适用于具有不同基因突变的患者。由于自闭症谱系障碍（ASD）的伤害性表型介于高敏感和低敏感之间，因此不同的突变可能以相反的方式影响回路。我们的研究结果证明，Shank2 表达识别了一个新的抑制性中间神经元子集，该子集参与减少伤害性刺激的传递，并且其不受控制的激活与疼痛超敏反应相关。我们提供的证据表明脊髓疼痛处理功能障碍可能导致自闭症谱系障碍的伤害性表型。我们的研究结果证明，Shank2 表达识别了一个新的抑制性中间神经元子集，该子集参与减少伤害性刺激的传递，并且其不受控制的激活与疼痛超敏反应相关。我们提供的证据表明脊髓疼痛处理功能障碍可能导致自闭症谱系障碍的伤害性表型。我们的研究结果证明，Shank2 表达识别了一个新的抑制性中间神经元子集，该子集参与减少伤害性刺激的传递，并且其不受控制的激活与疼痛超敏反应相关。我们提供的证据表明脊髓疼痛处理功能障碍可能导致自闭症谱系障碍的伤害性表型。