Studies on excitatory synaptic transmission regulated by neuronal ligand/receptor interactions

2014 Fiscal Year Final Research Report

• Project/Area Number: 25890021
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: National Institute for Physiological Sciences
• Principal Investigator: NORIHIKO Yokoi 生理学研究所, 細胞器官研究系, 特任助教 (50710969)
• Project Period (FY): 2013-08-30 – 2015-03-31
• Keywords: てんかん / ケミカルシャペロン / シナプス伝達 / タンパク質構造病 / タンパク質複合体 / モデルマウス / 治療薬 / 辺縁系脳炎

Outline of Final Research Achievements

LGI1 is a neuronal secreted protein, and its mutations cause an inherited form of human epilepsy, autosomal dominant lateral temporal lobe epilepsy (ADLTE). However, the patho-physiological functions of LGI1 still remain unclear. Here, we classified 22 reported LGI1 missense ADLTE mutations as either secretion defective or secretion competent, and we generated and analyzed two mouse models of ADLTE expressing the mutant protein representative of the two groups. Both mutations reduced synaptic LGI1-ADAM22 interaction by protein conformational defects in the mouse brain. A chemical chaperone, 4-phenylbutyrate, restored the folding of the secretion-deficient LGI1 mutant and its binding to ADAM22 and ameliorated the increased seizure susceptibility of the LGI1 mutant mice. This study establishes an essential role of the LGI1-ADAM22 interaction to regulate the brain excitability (Yokoi et al. Nat. Med. 2015, 21,19-26).

Free Research Field

神経科学