Munc18-1 and soluble NSF attachment protein receptors (SNAREs) are critical for synaptic vesicle fusion. Munc18-1 binds to the SNARE syntaxin-1 folded into a closed conformation and to SNARE complexes containing open syntaxin-1. Understanding which steps in fusion depend on the latter interaction and whether Munc18-1 competes with other factors such as complexins for SNARE complex binding is critical to elucidate the mechanisms involved. In this study, we show that lentiviral expression of Munc18-1 rescues abrogation of release in Munc18-1 knockout mice. We describe point mutations in Munc18-1 that preserve tight binding to closed syntaxin-1 but markedly disrupt Munc18-1 binding to SNARE complexes containing open syntaxin-1. Lentiviral rescue experiments reveal that such disruption selectively impairs synaptic vesicle priming but not Ca2+-triggered fusion of primed vesicles. We also find that Munc18-1 and complexin-1 bind simultaneously to SNARE complexes. These results suggest that Munc18-1 binding to SNARE complexes mediates synaptic vesicle priming and that the resulting primed state involves a Munc18-1–SNARE–complexin macromolecular assembly that is poised for Ca2+ triggering of fusion.

Recent interest in sensory gating in children with and without neuropsychological disorders has resulted in a number of studies and the results regarding the developmental trajectory of sensory gating are inconsistent. We investigated the maturational course of sensory gating in samples of typically developing children and children with sensory processing deficits (SPD) and compared their performance to adults. Besides gating ratios, we also examined the brain responses to conditioning and test click stimuli in the sensory gating paradigm separately to clarify if the changes in click amplitudes could explain the maturational change in the T/C ratio in children. Eighteen adults with no known disorders, 25 typical children, and 28 children with SPD participated in this study. The children ranged in ages between 5 and12 years. The three groups differed in their P50 and N100 ERP components. Both child groups displayed significantly less gating than the adults. Children with SPD demonstrated significantly less gating and more within-group variability compared to typical children. There were significant relationships between age and T/C ratios and between age and peakto-peak amplitude of the conditioning click in typical children but not in children with SPD. Typical children demonstrated significantly smaller brain response amplitudes to the clicks as compared to adults . These findings suggest that there is a maturational course of sensory gating in typical children and if there is a maturational trajectory in children with SPD it appears to be different than typical children. In addition, children with SPD were found to be lacking in their ability to filter out repeated auditory input and failed to selectively regulate their sensitivity to sensory stimuli. KeywordsSensory Gating; EEG/ERP; Children; Development; Sensory Processing Deficits Sensory gating is the brain's natural response to attenuate redundant or irrelevant sensory stimuli (Adler et al., 1982;Braff, Swerdlow, & Geyer, 1995;Freedman, Adler, & Waldo, 1987). The gating response is conceptualized as the brain's capacity to selectively regulate its sensitivity to sensory stimuli. Sensory Gating is a critical underlying psychophysiological and protective mechanism of brain function which directs processing resources to important environmental stimuli (Myles-Worsley et al., 1996). A number of neurotransmitters and Corresponding Author: Patricia L. Davies, 219 Occupational Therapy, Colorado State University, Fort Collins, CO 80523;; email address -E-mail: pdavies@lamar.colostate.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to ...