Prenatal exposure to valproic acid causes allodynia associated with spinal microglial activation
Prenatal exposure to valproic acid causes allodynia associated with spinal microglial activation
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DOI：
10.1016/j.neuint.2022.105415
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发表时间：
2022-08-26
影响因子：
4.2
通讯作者：
Ago, Yukio
中科院分区：
文献类型：
--
作者：
Imado, Eiji;Sun, Samnang;Ago, Yukio
自闭症谱系障碍 (ASD) 是一种神经发育障碍，其特征是社交沟通和社交互动缺陷以及存在受限、重复行为。此外，自闭症谱系障碍 (ASD) 患者通常会出现感觉处理困难。感觉异常包括对疼痛的敏感性升高或降低，但自闭症谱系障碍感觉表型的潜在机制仍不清楚。新的证据表明，小胶质细胞在形成和完善神经元回路中发挥着重要作用，从而有助于神经元可塑性和伤害性信号传导。在本研究中，我们研究了由产前暴露于丙戊酸（VPA）引起的 ASD 动物模型中年龄依赖性触觉敏感性，并随后评估了脊髓中小胶质细胞在疼痛处理中的参与。妊娠 ICR (CD1) 小鼠在胚胎第 12.5 天腹腔注射生理盐水或 VPA (500 mg/kg)。经过 VPA 治疗的母亲的雄性后代在 4 周和 8 周龄时均表现出机械性异常性疼痛。在产前 VPA 处理的小鼠脊髓背角中，离子化钙结合接头分子 1 阳性细胞的数量和染色强度增加，细胞体变大，表明小胶质细胞活化。 PLX3397（一种集落刺激因子 1 受体抑制剂）治疗 10 天后，产前暴露于 VPA 的成年小鼠的脊髓小胶质细胞数量减少，机械性异常性疼痛减轻。此外，鞘内注射 Mac-1-saporin（一种与 saporin 结合的抗 CD11b 抗体，可消耗小胶质细胞）可消除机械性异常性疼痛。这些发现表明，产前 VPA 治疗会引起异常性疼痛，而脊髓小胶质细胞会导致伤害性反应增加。
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social commu-nication and social interaction and the presence of restricted, repetitive behaviors. Additionally, difficulties in sensory processing commonly occur in ASD. Sensory abnormalities include heightened or reduced sensitivity to pain, but the mechanism underlying sensory phenotypes in ASD remain unknown. Emerging evidence suggests that microglia play an important role in forming and refining neuronal circuitry, and thus contribute to neuronal plasticity and nociceptive signaling. In the present study, we investigated the age-dependent tactile sensitivity in an animal model of ASD induced by prenatal exposure to valproic acid (VPA) and subsequently assessed the involvement of microglia in the spinal cord in pain processing. Pregnant ICR (CD1) mice were intraperitoneally injected with either saline or VPA (500 mg/kg) on embryonic day 12.5. Male offspring of VPA-treated mothers showed mechanical allodynia at both 4 and 8 weeks of age. In the spinal cord dorsal horn in prenatally VPA-treated mice, the numbers and staining intensities of ionized calcium-binding adapter molecule 1-positive cells were increased and the cell bodies became enlarged, indicating microglial activation. Treatment with PLX3397, a colony-stimulating factor 1 receptor inhibitor, for 10 days resulted in a decreased number of spinal microglia and attenuated mechanical allodynia in adult mice prenatally exposed to VPA. Additionally, intra-thecal injection of Mac-1-saporin, a saporin-conjugated anti-CD11b antibody to deplete microglia, abolished mechanical allodynia. These findings suggest that prenatal VPA treatment causes allodynia and that spinal microglia contribute to the increased nociceptive responses.