Genetic Markers of a Munc13 Protein Family Member, BAIAP3, Are Gender Specifically Associated with Anxiety and Benzodiazepine Abuse in Mice and Humans

Abstract

Anxiety disorders and substance abuse, including benzodiazepine use disorder, frequently occur together. Unfortunately, treatment of anxiety disorders still includes benzodiazepines, and patients with an existing comorbid benzodiazepine use disorder or a genetic susceptibility for benzodiazepine use disorder may be at risk of adverse treatment outcomes. The identification of genetic predictors for anxiety disorders, and especially for benzodiazepine use disorder, 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, with 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. By using a phenotype-based genetic association study, we identified 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 found 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 revealed an increase in basal network activity and an altered response to diazepam withdrawal. Thus, Baiap3/BAIAP3 is gender specifically associated with anxiety and benzodiazepine use disorder, and the analysis of Baiap3/BAIAP3-related functions may help elucidate mechanisms underlying the development of both disorders.

Sexual dimorphisms in adult human neural, mesoderm‐derived, and neural crest‐derived stem cells

“…Knockout of Baiap3 resulted in increased latency to reach walls in open field and higher freezing percentage. Surprisingly, the penetrance of this phenotype was observed to be sex-specific with an increased anxiety in females with much lower latency in the open field test and reduced visits to the center in female KO mice [61]. Furthermore, male diazepam-treated Baiap3 KO mice showed significantly faster improvement in the rotarod test, consistent with a more rapid development of tolerance to diazepam.…”

“…In terms of sex-specific differences in neuronal survival, Wojcik and coworkers described a mouse model with a knockout of brain-specific angiogenesis inhibitor I-associated protein 3 (Baiap3) [61]. Baiap3 is a member of the mammalian uncoordinated 13 protein family of synaptic regulators of neurotransmitter exocytosis.…”

“…Baiap3 is a member of the mammalian uncoordinated 13 protein family of synaptic regulators of neurotransmitter exocytosis. Finally, human BAIAP3 alleles were discovered that are associated with anxiety in women and benzodiazepine use disorder in men [61]. Knockout of Baiap3 resulted in increased latency to reach walls in open field and higher freezing percentage.…”

“…In addition, an increased anxiety was observed in both sexes, with a more pronounced effect in female KO mice. Finally, human BAIAP3 alleles were discovered that are associated with anxiety in women and benzodiazepine use disorder in men [61].…”

Extreme obesity is associated with variation in genes related to the circadian rhythm of food intake and hypothalamic signaling

“…BAIAP3 is a p53-induced protein that binds to the brain-specific angiogenesis inhibitor 1. Genetic variation in BAIAP3 was found to be associated with anxiety and benzodiazepine abuse (41). Associations between anxiety disorders and obesity have been reported, but their interplay seems very complex.…”