期刊
JOURNAL OF NEUROSCIENCE
卷 40, 期 12, 页码 2403-2415出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1514-19.2020
关键词
alpha2delta proteins; CACNA2D2; calcium channel; climbing fiber; Purkinje cell
资金
- Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development Merit Review Award [I01-BX002949]
- Department of Defense CDMRP Award [W81XWH-18 -1-0598]
- NIH [T32NS007466, R01NS080979, P30NS061800]
- OHSU Innovation Fund
- Murdock Charitable Trust
- NINDS [1R21NS102948]
alpha 2 delta proteins (Cacna2d1-4) are auxiliary subunits of voltage-dependent calcium channels that also drive synapse formation and maturation. Because cerebellar Purkinje cells (PCs) predominantly, if not exclusively, express one isoform of this family, alpha 2 delta-2 (Cacna2d2), we used PCs as a model system to examine roles of alpha 2 delta in excitatory synaptic function in male and female Cacna2d2 knock-out (KO) mice. Whole-cell recordings of PCs from acute cerebellar slices revealed altered climbing fiber (CF)-evoked complex spike generation, as well as increased amplitude and faster decay of CF-evoked EPSCs. CF terminals in the KO were localized more proximally on PC dendrites, as indicated by VGLUT2(+) immunoreactive puncta, and computational modeling demonstrated that the increased EPSC amplitude can be partly attributed to the more proximal location of CF terminals. In addition, CFs in KO mice exhibited increased multivesicular transmission, corresponding to greater sustained responses during repetitive stimulation, despite a reduction in the measured probability of release. Electron microscopy demonstrated that mutant CF terminals had twice as many vesicle release sites, providing a morphologic explanation for the enhanced glutamate release. Though KO CFs evoked larger amplitude EPSCs, the charge transfer was the same as wild-type as a result of increased glutamate reuptake, producing faster decay kinetics. Together, the larger, faster EPSCs in the KO explain the altered complex spike responses, which degrade information transfer from PCs and likely contribute to ataxia in Cacna2d2 KO mice. Our results also illustrate the multidimensional synaptic roles of alpha 2 delta proteins.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据