Most epilepsy genes encode ion channels, but the LGI1 gene responsible for Autosomal Dominant Partial Epilepsy with Auditory Features produces a secreted protein.LGI1 is suggested to regulate PSD-95 via ADAM22. However, no unbiased screen of LGI1 action has been conducted. Here, we searched for brain genes supporting high affinity LGI-1 binding. ADAM23 was the only LGI1 interactor identified. The related proteins, ADAM22 and ADAM11, but not ADAM12, bind LGI1. Neither ADAM23 nor ADAM11, nor some forms of ADAM22, contain PDZ-interacting sequences, suggesting PSD-95-independent mechanisms in ADPEAF. Because ADAMs modulate integrins, we examined LGI1 effect on neurite outgrowth. LGI1 increases outgrowth from wild type but not ADAM23-/-neurons. Furthermore, CA1 pyramidal neurons of ADAM23-/-hippocampi have reduced dendritic arborization. ADAM23-/-mice exhibit spontaneous seizures, while ADAM23+/-mice have decreased seizure thresholds. Thus, LGI1 binding to ADAM23 is necessary to correctly pattern neuronal morphology and altered anatomical patterning contributes to ADPEAF.