Epilepsy characterized by recurrent seizures is an intractable brain disorder and caused by the imbalance between excitatory and inhibitory synaptic transmission. Mutations of LGI1, a neuronal secreted protein, cause an inherited form of human epilepsy, autosomal dominant lateral temporal lobe epilepsy (ADLTE). Also, LGI1 is the main autoantigen for autoimmune limbic encephalitis, characterized by subacute memory impairment and seizures. Thus, LGI1 has emerged as an important determinant of brain excitability. We have reported that secreted LGI1 functions as a ligand for epilepsy-related synaptic transmembrane proteins, ADAM22 and ADAM23, and that loss of LGI1 reduces AMPA receptor-mediated synaptic transmission and causes lethal epilepsy in mice. However, the molecular mechanisms how LGI1 dysfunction causes epilepsy still remain unclear. Here, we studied LGI1 mutations identified in ADLTE pedigrees and classified them into secretion-defective and secretable mutations. When expressed in LGI1-knockout mice, both types of LGI1 mutant proteins could not rescue the epileptic phenotype, under the conditions wild-type LGI1 could rescue it. A secretion-defective LGI1 mutant protein was recognized by the ER quality control machinery and prematurely degraded, whereas a secretable mutant protein abnormally dimerized and was selectively defective in the binding to ADAM22, but not to ADAM23. Thus, both mutations reduced synaptic LGI1-ADAM22 interaction. Importantly, we found that a chemical compound restored LGI1 mutant protein folding and binding to ADAM22 both in vitro and in vivo, and ameliorated the seizure phenotype of LGI1 secretion-defective mutant mice. This study establishes an essential role for LGI1-ADAM22 interaction in determining brain excitability.