Genetic Markers of a Munc13 Protein Family Member, BAIAP3, Are Gender-Specifically Associated with Anxiety and Benzodiazepine Abuse in Mouse and Man
Anxiety disorders and substance abuse, including benzodiazepine use disorder (BUD), frequently occur together. Treatment of anxiety disorders unfortunately still includes benzodiazepines, and patients with an existing co-morbid BUD or a genetic susceptibility for BUD may be put at risk of adverse treatment outcomes. The identification of genetic predictors for anxiety disorders, and especially for BUD, could aid the selection of the best treatment option and improve clinical outcomes. 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, with a striking expression pattern in amygdalae, hypothalamus and periaqueductal gray. 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 hypothesized that genetic variation in human BAIAP3 may also be associated with anxiety. Using a phenotype-based genetic association study, we identify two human BAIAP3 single nucleotide polymorphism risk genotypes (AA for rs2235632, TT for rs1132358) 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 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 withdrawal. Thus, Baiap3/BAIAP3 is gender-specifically associated with anxiety and BUD, and the analysis of Baiap3/BAIAP3 related functions may help elucidate mechanisms underlying the development of both disorders.
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