D-Serine regulates cerebellar LTD and motor coordination through the δ2 glutamate receptor
D-Serine regulates cerebellar LTD and motor coordination through the δ2 glutamate receptor
复制标题
DOI：
10.1038/nn.2791
复制
发表时间：
2011-05-01
影响因子：
25
通讯作者：
Yuzaki, Michisuke
中科院分区：
文献类型：
--
作者：
Kakegawa, Wataru;Miyoshi, Yurika;Yuzaki, Michisuke
D-丝氨酸(D-Serine，D-Ser)是NMDA受体的内源性协同激动剂，调节前脑的神经传递和突触可塑性。D-丝氨酸也存在于出生后早期的小脑中。虽然D-丝氨酸在体外与谷氨酸受体(GluD2，GRID2)结合，但其生理意义尚不清楚。在这里，我们显示D-丝氨酸作为GluD2的内源性配体，调节未成熟小脑中平行纤维和浦肯野细胞之间突触的长期抑制(LTD)。D-丝氨酸主要由Bergmann胶质细胞在未成熟但未成熟的小脑平行纤维爆裂刺激后释放。D-Ser能迅速诱导野生型(而不是GRID2缺失的)浦肯野细胞内吞AMPA受体和相互封闭的LTD。此外，表达D-丝氨酸结合位点被破坏的突变GluD2的小鼠在发育过程中表现出LTD受损和运动协调失调。这些结果表明，胶质细胞D-丝氨酸通过与GluD2相互作用来调节突触可塑性和小脑功能。
D-Serine (D-Ser) is an endogenous co-agonist for NMDA receptors and regulates neurotransmission and synaptic plasticity in the forebrain. D-Ser is also found in the cerebellum during the early postnatal period. Although D-Ser binds to the delta 2 glutamate receptor (GluD2, Grid2) in vitro, its physiological significance has remained unclear. Here we show that D-Ser serves as an endogenous ligand for GluD2 to regulate long-term depression (LTD) at synapses between parallel fibers and Purkinje cells in the immature cerebellum. D-Ser was released mainly from Bergmann glia after the burst stimulation of parallel fibers in immature, but not mature, cerebellum. D-Ser rapidly induced endocytosis of AMPA receptors and mutually occluded LTD in wild-type, but not Grid2-null, Purkinje cells. Moreover, mice expressing mutant GluD2 in which the binding site for D-Ser was disrupted showed impaired LTD and motor dyscoordination during development. These results indicate that glial D-Ser regulates synaptic plasticity and cerebellar functions by interacting with GluD2.