Lewitus Gil M, Pribiag Horia, Duseja Rachna, St-Hilaire Michel, Stellwagen David
Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, Montreal, Quebec H3G 1A4, Canada, and McGill Psychiatry Program, Douglas Hospital Research Center, McGill University, Verdun, Quebec H3A 0G4, Canada.
J Neurosci. 2014 Apr 30;34(18):6146-55. doi: 10.1523/JNEUROSCI.3481-13.2014.
Elevation of inflammatory cytokines in the striatum precedes symptoms in a number of motor dysfunctions, but it is unclear whether this is part of the disease process or an adaptive response to the pathology. In pyramidal cells, TNFα drives the insertion of AMPA-type glutamate receptors into synapses, and contributes to the homeostatic regulation of circuit activity in the developing neocortex. Here we demonstrate that in the mouse dorsolateral striatum, TNFα drives the internalization of AMPARs and reduces corticostriatal synaptic strength, dephosphorylates DARPP-32 and GluA1, and results in a preferential removal of Ca(2+)-permeable AMPARs. Striatal TNFα signaling appears to be adaptive in nature, as TNFα is upregulated in response to the prolonged blockade of D2 dopamine receptors and is necessary to reduce the expression of extrapyramidal symptoms induced by chronic haloperidol treatment. These data indicate that TNFα is a regulator of glutamatergic synaptic strength in the adult striatum in a manner distinct from its regulation of synapses on pyramidal cells and mediates an adaptive response during pathological conditions.
在许多运动功能障碍中，纹状体内炎性细胞因子的升高先于症状出现，但尚不清楚这是疾病过程的一部分还是对病理状态的适应性反应。在锥体细胞中，肿瘤坏死因子α（TNFα）促使AMPA型谷氨酸受体插入突触，并有助于发育中的新皮质中回路活动的稳态调节。在此，我们证明，在小鼠背外侧纹状体中，TNFα促使AMPA受体内化并降低皮质纹状体突触强度，使多巴胺-和3',5'-环磷腺苷调节的磷酸蛋白-32（DARPP-32）和谷氨酸受体亚基A1（GluA1）去磷酸化，并导致优先去除钙通透性AMPA受体。纹状体TNFα信号似乎本质上具有适应性，因为TNFα在D2多巴胺受体长期阻断后上调，并且对于减少慢性氟哌啶醇治疗诱导的锥体外系症状的表达是必需的。这些数据表明，TNFα以不同于其对锥体细胞突触调节的方式调节成年纹状体中谷氨酸能突触强度，并在病理状态下介导适应性反应。
