Data_Sheet_5_Neural mechanism underlies CYLD modulation of morphology and synaptic function of medium spiny neurons in dorsolateral striatum.xlsx

Although the deubiquitinase cylindromatosis (CYLD), an abundant protein in the postsynaptic density fraction, plays a crucial role in mediating the synaptic activity of the striatum, the precise molecular mechanism remains largely unclear. Here, using a Cyld-knockout mouse model, we demonstrate that CYLD regulates dorsolateral striatum (DLS) neuronal morphology, firing activity, excitatory synaptic transmission, and plasticity of striatal medium spiny neurons via, likely, interaction with glutamate receptor 1 (GluA1) and glutamate receptor 2 (GluA2), two key subunits of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). CYLD deficiency reduces levels of GluA1 and GluA2 surface protein and increases K63-linked ubiquitination, resulting in functional impairments both in AMPAR-mediated excitatory postsynaptic currents and in AMPAR-dependent long-term depression. The results demonstrate a functional association of CYLD with AMPAR activity, which strengthens our understanding of the role of CYLD in striatal neuronal activity.

尽管去泛素化酶圆柱瘤蛋白（CYLD）作为突触后致密体组分（postsynaptic density fraction）中的丰富蛋白，在介导纹状体（striatum）突触活动中发挥关键作用，但其确切的分子机制仍在很大程度上未被阐明。本研究利用CYLD基因敲除小鼠模型，证实CYLD可能通过与α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPARs）的两个关键亚基——谷氨酸受体1（GluA1）与谷氨酸受体2（GluA2）相互作用，调控背外侧纹状体（DLS）中型多棘神经元的形态、放电活动、兴奋性突触传递及可塑性。CYLD缺失会降低GluA1与GluA2的表面蛋白水平，并增强K63位连接的泛素化修饰，进而导致AMPAR介导的兴奋性突触后电流以及AMPAR依赖的长时程抑制出现功能损伤。本研究结果证实了CYLD与AMPAR活性之间的功能性关联，这进一步加深了我们对CYLD在纹状体神经元活动中所发挥作用的理解。