Physiological role of the novel neuromodulator "LGI family"

突触传递的调节机制应该有助于理解大脑疾病的病因，如癫痫和痴呆症。到目前为止，我们已经确定癫痫相关的LGI1和ADAM22是新的配体/受体，并表明LGI1通过ADAM22增强AMPA受体介导的突触传递(Fukata等人，科学，2010年)。为了阐明LGI家族蛋白在脑功能中的生理作用，我们建立了LGI1基因敲除(KO)小鼠，发现LGI1KO小鼠表现出致死性癫痫表型(Fukata等人，PNAS 2010)。我们发现LGI3不与ADAM22结合，也不能拯救LGI1 KO小鼠，在神经元表达LGI1的情况下可以拯救它。有趣的是，LGI4与ADAM22结合，并部分挽救了LGI1 KO小鼠的癫痫。此外，LGI2截断可导致狗出现缓解性局灶性癫痫(Seppala等人，PLoS Genet 2011)。因此，我们发现LGI1、2和4共享其受体ADAM22和23，并调节不同脑区的神经元兴奋性，而LGI3可能通过未知的受体在大脑中发挥不同的功能。因此，我们在阐明LGI家族在体内的病理生理作用方面取得了稳定和持续的进展。

Regulatory mechanisms for synaptic transmission should lead to understanding the etiology of brain disorders, such as epilepsy and dementia. So far, we have identified epilepsy-related LGI1 and ADAM22 as the novel ligand/receptor, and showed LGI1 enhances AMPA receptor-mediated synaptic transmission through ADAM22(Fukata et al, Science 2010). To clarify the physiological role of LGI family proteins especially in brain functions, we generated LGI1 knockout(KO) mice and found that LGI1 KO mice showed lethal epileptic phenotype(Fukata et al, PNAS 2010). We found that LGI3 did not bind to ADAM22 and could not rescue LGI1 KO mice, under the condition in which neuronal LGI1 expression could rescue it. Interestingly, LGI4 bound to ADAM22 and partly rescued the epilepsy of LGI1 KO mice. In addition, LGI2 truncation causes a remitting focal epilepsy in dogs(Seppala et al, PLoS Genet 2011). Thus, we found that LGI1, 2, and 4 share their receptors ADAM22 and 23 and regulate the neuronal excitability in different brain regions, while LGI3 may differently function in the brain through the unidentified receptor. Thus, we have made steady and continual progress on clarifying the patho-physiological roles of LGI family in vivo.