Genetic Markers of a Munc13 Protein Family Member, BAIAP3, Are Gender-Specifically Associated with Anxiety and Benzodiazepine Abuse in Mouse and Man
ABSTRACT 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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ABSTRACT: The X-chromosomal MECP2/Mecp2 gene encodes methyl-CpG-binding protein 2, a transcriptional activator and repressor regulating many other genes. We discovered in male FVB/N mice that mild (~50%) transgenic overexpression of Mecp2 enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 modulates aggressive social behavior. To test this hypothesis in humans, we performed a phenotype-based genetic association study (PGAS) in >1000 schizophrenic individuals. We found MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3′UTR) associated with aggression, with the G and C carriers, respectively, being more aggressive. This finding was replicated in an independent schizophrenia cohort. Allele-specific MECP2 mRNA expression differs in peripheral blood mononuclear cells by ~50% (rs2734647: C > T). Notably, the brain-expressed, species-conserved miR-511 binds to MECP2 3′UTR only in T carriers, thereby suppressing gene expression. To conclude, subtle MECP2/Mecp2 expression alterations impact aggression. While the mouse data provides evidence of an interaction between genetic background and mild Mecp2 overexpression, the human data convey means by which genetic variation affects MECP2 expression and behavior.EMBO Molecular Medicine 03/2014; DOI:10.1002/emmm.201303744 · 8.25 Impact Factor
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ABSTRACT: Ribbon synapses of cochlear inner hair cells (IHCs) employ efficient vesicle replenishment to indefatigably encode sound. In neurons, neuroendocrine and immune cells, vesicle replenishment depends on proteins of the mammalian uncoordinated 13 (Munc13) and Ca(2+)-dependent activator proteins for secretion (CAPS) families, which prime vesicles for exocytosis. Here, we tested whether Munc13 and CAPS proteins also regulate exocytosis in mouse IHCs by combining immunohistochemistry with auditory systems physiology and IHC patch-clamp recordings of exocytosis in mice lacking Munc13 and CAPS isoforms. Surprisingly, we did not detect Munc13 or CAPS proteins at IHC presynaptic active zones (AZs) and found normal IHC exocytosis as well as auditory brainstem responses (ABRs) in Munc13 and CAPS deletion mutants. Instead, we show that otoferlin, a C2-domain protein critical for vesicular fusion and replenishment in IHCs, clusters at the plasma membrane of the presynaptic AZ. Electron tomography of otoferlin-deficient IHC synapses revealed a reduction of short tethers holding vesicles at the AZ, which might be a structural correlate of impaired vesicle priming in otoferlin-deficient IHCs. We conclude that IHCs use an unconventional priming machinery that involves otoferlin.Journal of Cell Science 01/2015; 128(4). DOI:10.1242/jcs.162099 · 5.33 Impact Factor
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ABSTRACT: Munc13-3 is a member of the Munc13 family of synaptic vesicle priming proteins and mainly expressed in cerebellar neurons. Munc13-3 null mutant (Munc13-3 −/−) mice show decreased synaptic release probability at parallel fiber to Purkinje cell, granule cell to Golgi cell, and granule cell to basket cell synapses and exhibit a motor learning deficit at highest rotarod speeds. Since we detected Munc13-3 immunoreactivity in the dentate gyrus, as reported here for the first time, and current studies indicated a crucial role for the cerebellum in hippocampus-dependent spatial memory, we systematically investigated Munc13-3 −/− mice versus wild-type littermates of both genders with respect to hippocampus-related cognition and a range of basic behaviors, including tests for anxiety, sensory functions, motor performance and balance, sensorimotor gating, social interaction and competence, and repetitive and compulsive behaviors. Neither basic behavior nor hippocampus-dependent cognitive performance, evaluated by Morris water maze, hole board working and reference memory, IntelliCage-based place learning including multiple reversals, and fear conditioning, showed any difference between genotypes. However, consistent with a disturbed cerebellar reflex circuitry, a reliable reduction in the acoustic startle response in both male and female Munc13-3 −/− mice was found. To conclude, complete deletion of Munc13-3 leads to a robust decrease in the acoustic startle response. This readout of a fast cerebellar reflex circuitry obviously requires synaptic vesicle priming by Munc13-3 for full functionality, in contrast to other behavioral or cognitive features, where a nearly perfect compensation of Munc13-3 deficiency by related synaptic proteins has to be assumed.The Cerebellum 01/2015; 14(3). DOI:10.1007/s12311-015-0645-0 · 2.86 Impact Factor