Baiap3 as a genetic marker associated with anxiety and benzodiazepine abuse in mouse and man

The brain specific angiogenesis inhibitor I-associated protein 3 (Baiap3) is a member of the mammalian uncoordinated-13 (Munc13) protein family of synaptic regulators of neurotransmitter exocytosis. Baiap3 has a striking expression pattern in amygdalae, hypothalamus and periaqueductal gray. We identify Baiap3 as a first genetic risk marker for anxiety and benzodiazepine use disorder in mice and humans. Deletion of Baiap3 in mice leads to enhanced seizure propensity and increased anxiety, the latter being more pronounced in female than in male animals. We further identify human BAIAP3 risk genotypes that show a significant association with anxiety in women and, surprisingly, with benzodiazepine abuse in men. Returning to mice, we find that male, but not female Baiap3 knockout (KO) mice develop tolerance to diazepam more quickly than control animals. Analysis of cultured Baiap3 KO hypothalamus slices reveals an increase in basal network activity and an altered response to diazepam. Thus, Baiap3/BAIAP3 is the first gene shown to be gender-specifically associated with increased anxiety and benzodiazepine abuse in mice and humans. Further analysis of Baiap3/BAIAP3-related functions may therefore help elucidate mechanisms underlying the development of both disorders.