Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, 734-8553, Japan; Department of Dental Anesthesiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, 734-8553, Japan.
School of Dentistry, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, 734-8553, Japan; Faculty of Odonto-Stomatology, University of Health Sciences, #73, Monivong Blvd., Sangkat Sras Chak, Khan Daun Penh, Phnom Penh, 12201, Cambodia.
Neurochem Int. 2022 Nov;160:105415. doi: 10.1016/j.neuint.2022.105415. Epub 2022 Aug 24.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication 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, intrathecal 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.
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方面的缺陷，以及受限的、重复的行为。此外，ASD 通常存在感觉处理困难。感觉异常包括对疼痛的敏感性增加或降低，但 ASD 中感觉表型的潜在机制尚不清楚。新出现的证据表明，小胶质细胞在形成和精炼神经元回路方面发挥着重要作用，从而有助于神经元可塑性和伤害性信号传递。在本研究中，我们研究了产前暴露于丙戊酸 (VPA) 诱导的 ASD 动物模型中的年龄依赖性触觉敏感性，随后评估了脊髓中小胶质细胞在疼痛处理中的参与。怀孕的 ICR (CD1) 小鼠在胚胎第 12.5 天经腹腔注射生理盐水或 VPA (500mg/kg)。VPA 处理母亲的雄性后代在 4 周和 8 周龄时均表现出机械性痛觉过敏。在产前 VPA 处理的小鼠脊髓背角中，离子钙结合衔接分子 1 阳性细胞的数量和染色强度增加，细胞体增大，表明小胶质细胞活化。用集落刺激因子 1 受体抑制剂 PLX3397 处理 10 天导致成年小鼠脊髓中小胶质细胞数量减少，并减轻了产前 VPA 暴露引起的机械性痛觉过敏。此外，鞘内注射 Mac-1-saporin，一种与 saporin 结合的抗 CD11b 抗体以耗尽小胶质细胞，可消除机械性痛觉过敏。这些发现表明，产前 VPA 处理会导致痛觉过敏，而脊髓小胶质细胞有助于增加伤害性反应。
