title: 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.
authors.affiliation: Max Planck Institute of Experimental Medicine, Department of Molecular Neurobiology, Göttingen, Germany. wojcik@em.mpg.de
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Wojcik
authors.forename: Martesa
authors.initials: M
authors.lastname: Tantra
authors.forename: Beata
authors.initials: B
authors.lastname: Stepniak
authors.forename: Kwun-Nok M
authors.initials: KN
authors.lastname: Man
authors.forename: Katja
authors.initials: K
authors.lastname: Müller-Ribbe
authors.forename: Martin
authors.initials: M
authors.lastname: Begemann
authors.forename: Anes
authors.initials: A
authors.lastname: Ju
authors.forename: Sergi
authors.initials: S
authors.lastname: Papiol
authors.forename: Anja
authors.initials: A
authors.lastname: Ronnenberg
authors.forename: Artem
authors.initials: A
authors.lastname: Gurvich
authors.forename: Yong
authors.initials: Y
authors.lastname: Shin
authors.forename: Iris
authors.initials: I
authors.lastname: Augustin
authors.forename: Nils
authors.initials: N
authors.lastname: Brose
authors.forename: Hannelore
authors.initials: H
authors.lastname: Ehrenreich
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage; D000927:Anticonvulsants / Q000008:administration & dosage; D001007:Anxiety / Q000235:genetics* / Q000503:physiopathology; D001522:Behavior, Animal; D003975:Diazepam / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007031:Hypothalamus / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008874:Midazolam / Q000008:administration & dosage*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010433:Pentylenetetrazole; D020641:Polymorphism, Single Nucleotide; D011597:Psychomotor Performance; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D012737:Sex Factors; D019966:Substance-Related Disorders / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology
chemical_list: D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; C585199:BAIAP3 protein, human; C585200:Baiap3 protein, mouse; D009419:Nerve Tissue Proteins; D003975:Diazepam; D008874:Midazolam; D010433:Pentylenetetrazole