Orefice Lauren L, Zimmerman Amanda L, Chirila Anda M, Sleboda Steven J, Head Joshua P, Ginty David D
Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
Cell. 2016 Jul 14;166(2):299-313. doi: 10.1016/j.cell.2016.05.033. Epub 2016 Jun 9.
Patients with autism spectrum disorders (ASDs) commonly experience aberrant tactile sensitivity, yet the neural alterations underlying somatosensory dysfunction and the extent to which tactile deficits contribute to ASD characteristics are unknown. We report that mice harboring mutations in Mecp2, Gabrb3, Shank3, and Fmr1 genes associated with ASDs in humans exhibit altered tactile discrimination and hypersensitivity to gentle touch. Deletion of Mecp2 or Gabrb3 in peripheral somatosensory neurons causes mechanosensory dysfunction through loss of GABAA receptor-mediated presynaptic inhibition of inputs to the CNS. Remarkably, tactile defects resulting from Mecp2 or Gabrb3 deletion in somatosensory neurons during development, but not in adulthood, cause social interaction deficits and anxiety-like behavior. Restoring Mecp2 expression exclusively in the somatosensory neurons of Mecp2-null mice rescues tactile sensitivity, anxiety-like behavior, and social interaction deficits, but not lethality, memory, or motor deficits. Thus, mechanosensory processing defects contribute to anxiety-like behavior and social interaction deficits in ASD mouse models. PAPERCLIP.
自闭症谱系障碍（ASD）患者通常会出现异常的触觉敏感性，但体感功能障碍背后的神经改变以及触觉缺陷对ASD特征的影响程度尚不清楚。我们报告称，携带与人类ASD相关的Mecp2、Gabrb3、Shank3和Fmr1基因突变的小鼠表现出触觉辨别能力改变以及对轻柔触摸的超敏反应。外周体感神经元中Mecp2或Gabrb3的缺失通过丧失GABAA受体介导的对中枢神经系统输入的突触前抑制而导致机械感觉功能障碍。值得注意的是，在发育过程中而非成年期，体感神经元中Mecp2或Gabrb3缺失导致的触觉缺陷会引起社交互动缺陷和焦虑样行为。仅在Mecp2基因敲除小鼠的体感神经元中恢复Mecp2表达可挽救触觉敏感性、焦虑样行为和社交互动缺陷，但不能挽救致死性、记忆或运动缺陷。因此，机械感觉处理缺陷导致了ASD小鼠模型中的焦虑样行为和社交互动缺陷。回形针。
