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首页> 外文学位 >Altered neuronal circuits as the basis for ADPEAF epilepsy: LGI1 binding to ADAM23 is required for dendritic morphology.
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Altered neuronal circuits as the basis for ADPEAF epilepsy: LGI1 binding to ADAM23 is required for dendritic morphology.

机译：改变的神经元回路作为ADPEAF癫痫的基础：树突形态需要LGI1与ADAM23结合。

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摘要

Human epilepsy assumes diverse clinical courses and has many causes, including genetic predisposition. While nearly all human epilepsy-related genes encode ion channels, the mutant gene responsible for Autosomal Dominant Partial Epilepsy with Auditory Features (ADPEAF) does not. The gene causing 50% of ADPEAF cases encodes the LGI1 protein. Various mechanisms for LGI1 mutant-dependent epilepsy have been suggested. Schulte et al. (2006) reported that intracellular LGI1 modulated the inactivation rate of a voltage-gated K channel. However, numerous groups have shown that the majority of LGI1 protein is secreted. In an alternate pathway, Fukata et al. (2006) found that secreted LGI1 can bind to a rare isoform of transmembrane ADAM22 to alter PSD-95 and hence AMPA-receptor mediated synaptic transmission. However, the majority of ADAM22 isoforms and all of the related LGI1-binding ADAMs do not contain the PDZ-binding motifs capable of interacting with PSD-95. No unbiased genome based screen for LGI1 interactors has been conducted and no ion channel independent mechanism for LGI1 action in ADPEAF has been suggested.We screened a mouse cDNA library with LGI1 as a ligand and isolated ADAM23 as a high affinity interactor. We find that LGI1 also binds the closely related ADAM22 and ADAM11, but not ADAM12. We also show that LGI1 increases outgrowth of hippocampal and cortical neurons in-vitro, and that neurons from mice lacking ADAM23 show reduced outgrowth stimulation by LG11. We show that ADAM23 -/- mice exhibit clinical seizures in the neonatal period and adult ADAM23 +/- mice have decreased threshold to chemically induced seizures. Furthermore, pyramidal neurons in the CA1 region of ADAM23 -/- mice hippocampi have significantly reduced area of dendritic arborization. We conclude that LGI1 binding to ADAM22/23/11 is necessary to correctly pattern neuronal morphology and prevent an anatomically engendered epilepsy in ADPEAF.
机译：人类癫痫病的临床过程多种多样，并有许多原因，包括遗传易感性。尽管几乎所有与人类癫痫症相关的基因都编码离子通道，但负责常染色体显性部分性癫痫并具有听觉特征的突变基因却没有。引起50％ADPEAF病例的基因编码LGI1蛋白。已经提出了多种LGI1突变体依赖型癫痫的机制。舒尔特等。 （2006）报道细胞内LGI1调节电压门控K通道的失活速率。但是，许多研究表明，大多数LGI1蛋白是分泌的。在另一种途径中，Fukata等。 （2006年）发现，分泌的LGI1可以与跨膜ADAM22的罕见同工型结合，从而改变PSD-95，从而改变AMPA受体介导的突触传递。但是，大多数ADAM22同工型和所有相关的与LGI1结合的ADAM不包含能够与PSD-95相互作用的PDZ结合基序。没有进行过基于基因组的LGI1相互作用体的筛选，也没有提出离子通道独立的LGI1作用于ADPEAF的机制。我们筛选了以LGI1为配体的小鼠cDNA文库，并分离了ADAM23作为高亲和力的相互作用体。我们发现LGI1还绑定了密切相关的ADAM22和ADAM11，但没有绑定ADAM12。我们还显示，LGI1会增加海马和皮质神经元的体外生长，而缺少ADAM23的小鼠的神经元显示出LG11降低的生长刺激。我们显示，ADAM23-/-小鼠在新生儿期表现出临床惊厥，而成年ADAM23 +/-小鼠的化学诱发惊厥阈值降低。此外，ADAM23-/-小鼠海马CA1区的锥体神经元的树突状乔化面积显着减少。我们得出结论，将LGI1与ADAM22 / 23/11结合对于正确设置神经元形态并防止ADPEAF中解剖学引起的癫痫病是必要的。

著录项

  • 作者

    Owuor, Katherine.;

  • 作者单位

    Yale University.;

  • 授予单位 Yale University.;
  • 学科 Biology Neuroscience.Chemistry Biochemistry.Biology Genetics.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 85 p.
  • 总页数 85
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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