Ethanol Regulates Presynaptic Activity and Sedation through Presynaptic Unc13 Proteins in Drosophila.

Ethanol has robust effects on presynaptic activity in many neurons, however, it is not yet clear how this drug acts within this compartment to change neural activity, nor the significance of this change on behavior and physiology in vivo. One possible presynaptic effector for ethanol is the Munc13-1 protein. Herein, we show that ethanol binding to the rat Munc13-1 C1 domain, at concentrations consistent with binge exposure, reduces diacylglycerol (DAG) binding. The inhibition of DAG binding is predicted to reduce the activity of Munc13-1 and presynaptic release. In Drosophila, we show that sedating concentrations of ethanol significantly reduce synaptic vesicle release in olfactory sensory neurons (OSNs), while having no significant impact on membrane depolarization and Ca2+ influx into the presynaptic compartment. These data indicate that ethanol targets the active zone in reducing synaptic vesicle exocytosis. Drosophila, haploinsufficent for the Munc13-1 ortholog Dunc13, are more resistant to the effect of ethanol on presynaptic inhibition. Genetically reducing the activity of Dunc13 through mutation or expression of RNAi transgenes also leads to a significant resistance to the sedative effects of ethanol. The neuronal expression of Munc13-1 in heterozygotes for a Dunc13 loss-of-function mutation can largely rescue the ethanol sedation resistance phenotype, indicating a conservation of function between Munc13-1 and Dunc13 in ethanol sedation. Hence, reducing Dunc13 activity leads to naïve physiological and behavioral resistance to sedating concentrations of ethanol. We propose that reducing Dunc13 activity, genetically or pharmacologically by ethanol binding to the C1 domain of Munc13-1/Dunc13, promotes a homeostatic response that leads to ethanol tolerance.

Cone Beam Computed Tomography of mandibular bone density in non-diabetic vs. diabetic populations.

BACKGROUND: The successful placement of dental implant largely depends on the properties of alveolar bone at the recipient site. Systemic conditions such as diabetes mellitus could impair bone quality and compromise implant treatment. However, limited information in this area exists so far. The objective of the study is to use cone beam computed tomography (CBCT) to assess mandibular bone mineral density (BMD) in diabetic and non-diabetic populations. METHODS: The patients who had CBCT scans in the school from 2011-2015 were screened, and 14 diabetic and 14 non- diabetic patients with matched age, gender, and ethnicity were recruited. BMD was measured on reconstructed CBCT sagittal views at 7 mm2 rectangular areas on 6 sites for each patient. For cortical bone, BMD was measured at the inferior border of mandible in the midline and between the first and second premolar bilaterally. For cancellous bone, BMD was measured in the midline of mandible halfway between the lingual foramen/canal and the inferior border of mandible, and at the premolar area halfway between the mandibular canal and the inferior border of mandible bilaterally. For diabetic patients, the glycosylated hemoglobin (HbAlc) values were obtained after informed consent. Statistical significant difference was set at p <0.05. The correlation between BMD and the age, gender, and HbAlc value of the patients was analyzed. An institutional IRB approval was obtained for the study. RESULTS: Diabetic patients had significantly lower cancellous BMD than non-diabetic subjects in the posterior mandibles (367 vs. 430, p<0.05). For both groups, cancellous BMD in the posterior mandible was significantly lower than that of anterior mandible. CONCLUSIONS: Diabetic patients have decreased BMD in the posterior mandible which could adversely affect implant placement at these areas.