Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer
Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer
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DOI：
10.1523/jneurosci.19-14-06027.1999
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发表时间：
1999-07-15
影响因子：
5.3
通讯作者：
Kano, M
中科院分区：
文献类型：
--
作者：
Hashimoto, K;Fukaya, M;Kano, M
自发性隐性突变小鼠stargazer （stg）在出生后14天左右开始出现共济失调，并在成年后的经典眨眼条件反射习得中表现出严重的障碍。这些异常归因于脑源性神经营养因子（BDNF）的特异性减少以及随后小脑颗粒细胞（GCs）中TrkB受体信号传导的缺陷。在stg突变体小脑中，我们发现苔藓纤维（MF）到GC突触的EPSCs缺乏ampa型谷氨酸受体介导的快速成分，尽管有正常的NMDA受体介导的慢速成分。stg突变体GCs对外源AMPA的敏感性大大降低，而对NMDA的敏感性不变。在突触向GCs传递过程中，MF末端谷氨酸释放正常。相比之下，AMPA受体介导的EP-SCs在stg突变海马CA1锥体细胞中是正常的。因此，在stg突变型GC中，突触后AMPA受体功能选择性受损，尽管stg GC中四个AMPA受体亚基基因的转录与野生型GC相当。我们还检查了BDNF敲除小鼠的小脑，发现它们的MF-GC突触具有正常的AMPA受体介导的EPSC成分。因此，stg突变体GC中AMPA受体功能受损不太可能是由于BDNF-TrkB信号的减少。这些结果提示，MF - GC突触传递的缺陷是导致stg突变小鼠小脑功能障碍的主要因素。
The spontaneous recessive mutant mouse stargazer (stg) begins to show ataxia around postnatal day 14 and display a severe impairment in the acquisition of classical eyeblink conditioning in adulthood. These abnormalities have been attributed to the specific reduction in brain-derived neurotrophic factor (BDNF) and the subsequent defect in TrkB receptor signaling in cerebellar granule cells (GCs). In the stg mutant cerebellum, we found that EPSCs at mossy fiber (MF) to GC synapses are devoid of the fast component mediated by AMPA-type glutamate receptors despite the normal slow component mediated by NMDA receptors. The sensitivity of stg mutant GCs to exogenously applied AMPA was greatly reduced, whereas that to NMDA was unchanged. Glutamate release from MF terminals during synaptic transmission to GCs appeared normal. By contrast, AMPA receptor-mediated EP-SCs were normal in CA1 pyramidal cells of the stg mutant hippocampus. Thus, postsynaptic AMPA receptor function was selectively impaired in stg mutant GCs, although the transcription of four AMPA receptor subunit: genes in the stg GC was comparable to the wild-type GC. We also examined the cerebellum of BDNF knockout mice and found that their MF-GC synapses had a normal AMPA receptor-mediated EPSC component. Thus, the impaired AMPA receptor function in the stg mutant GC is not likely to result from the reduced BDNF-TrkB signaling. These results suggest that the defect in MF to GC synaptic transmission is a major factor that causes the cerebellar dysfunction in the stg mutant mouse.