Yabumoto Taiki, Kochoian Brik A, Coletta Stefano, Laur Oskar, Huang Xinping, Bure Cassandra A, Ware Christopher, Jin Peng, Traynelis Stephen F, Papa Stella M
Emory National Primate Research Center, Emory University, Atlanta, 30329, Georgia.
Department of Microbiology/Immunology and Emory Integrated Genomics Core, Emory University School of Medicine, Atlanta, 30322, Georgia.
Neuropharmacology. 2025 Jul 29;279:110616. doi: 10.1016/j.neuropharm.2025.110616.
L-DOPA-induced dyskinesia (LID) is a common disabling complication of long-term L-DOPA therapy in Parkinson's disease (PD). LID development is associated with maladaptive plasticity mechanisms in striatal circuits contributed by dysregulated dopamine and glutamate signaling. Upregulation of the NMDAR subunit 2A (GluN2A) over chronic L-DOPA treatment is thought to play a role in corticostriatal synaptic changes. We investigated the motor effects of selective GluN2A gene silencing by injecting a shRNA vector in the striatum of hemiparkinsonian rats. Striatal GluN2A knockdown significantly reduced abnormal involuntary movements (AIMs) while sustaining the therapeutic benefit of L-DOPA. These findings suggest that targeted adjustments of striatal NMDAR subunit composition may be a promising strategy for managing the long-term therapy of PD.
左旋多巴诱发的异动症（LID）是帕金森病（PD）长期左旋多巴治疗常见的致残性并发症。LID的发生与纹状体回路中适应性不良的可塑性机制有关，这是由多巴胺和谷氨酸信号失调所致。长期左旋多巴治疗导致N-甲基-D-天冬氨酸受体（NMDAR）亚基2A（GluN2A）上调，被认为在皮质纹状体突触变化中起作用。我们通过向偏侧帕金森病大鼠纹状体注射短发夹RNA（shRNA）载体，研究了选择性沉默GluN2A基因的运动效应。纹状体GluN2A基因敲低显著减少了异常不自主运动（AIMs），同时维持了左旋多巴的治疗效果。这些发现表明，针对性调整纹状体NMDAR亚基组成可能是管理帕金森病长期治疗的一种有前景的策略。
