Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy.
Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy.
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作者：
在出生后早期，一个中枢神经元突触的子集通过未解决的机制被协调地修剪和成熟。我们报告，人类癫痫基因LGI 1，突变的常染色体显性遗传侧颞叶癫痫（ADLTE），介导这一过程在海马。我们将编码（1）ADLTE截短突变型LGI 1（835 delC）和（2）过量野生型LGI 1蛋白的全长基因导入转基因小鼠。我们发现，正常的出生后Kv 1通道依赖的突触前释放概率的下调和Src激酶相关的突触后NR 2B/NR 2A比值的降低被ADLTE突变体LGI 1阻止，相反，被过量的野生型LGI 1放大。同时，突变型LGI 1抑制树突修剪，增加树突棘密度，显著增加兴奋性传递。相比之下，抑制性传播则不受影响。此外，突变LGI 1促进癫痫样放电在体外和点燃癫痫发作在体内与部分GABAA受体阻滞。因此，LGI 1代表了第一个突变的人类基因，通过受损的神经元能回路成熟来促进癫痫。
A subset of central glutamatergic synapses are coordinatelypruned and matured by unresolved mechanisms during early postnatal life. We report that human epilepsy gene LGI1, mutated in autosomal dominant lateral temporal lobe epilepsy (ADLTE), mediates this process in hippocampus. We introduced full-length genes encoding (1) ADLTE truncated mutant LGI1 (835delC) and (2) excess wild-type LGI1 proteins into transgenic mice. We discovered that the normal postnatal Kv1 channel-dependent down-regulation of presynaptic release probability and Src kinase-related decrease of postsynaptic NR2B/NR2A ratio were arrested by ADLTE mutant LGI1, and contrastingly, were magnified by excess wild-type LGI1. Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory transmission. Inhibitory transmission, by contrast, was unaffected. Furthermore, mutant LGI1 promoted epileptiform discharge in vitro and kindling epileptogenesis in vivo with partial GABAA receptor blockade. Thus, LGI1 represents the first human gene mutated to promote epilepsy through impaired glutamatergic circuit maturation.
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影响因子：
2.5
作者：
Liu, YB;Lio, PA;Trommer, BL
通讯作者：
Trommer, BL
影响因子：
64.8
作者：
Chavis, P;Westbrook, G
通讯作者：
Westbrook, G
影响因子：
30.8
作者：
Kalachikov, S;Evgrafov, O;Gilliam, TC
通讯作者：
Gilliam, TC
DOI：
10.1073/pnas.95.25.15037
发表时间：
1998-12-08
影响因子：
11.1
作者：
Meiri, N;Sun, MK;Alkon, DL
通讯作者：
Alkon, DL
影响因子：
5.3
作者：
Charych, Erik I.;Akum, Barbara F.;Firestein, Bonnie L.
通讯作者：
Firestein, Bonnie L.