• Alfredo Ramos-Miguel, Kristina Gicas, Jehan Alamri, Clare L Beasley, Andrew J Dwork, J John Mann, Gorazd Rosoklija, Fang Cai, Weihong Song, Alasdair M Barr, and William G Honer.
• BC Mental Health and Addictions Research Institute, 938 West 28th Ave, Vancouver, BC V5Z 4H4, Canada; Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 2A1, Canada; Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Biscay, Spain.
• Neuroscience. 2019 Nov 10; 420: 112-128.

AbstractRecent studies associated schizophrenia with enhanced functionality of the presynaptic SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex. Altered degradation pathways of the three core SNARE proteins: synaptosomal-associated protein 25 (SNAP25), syntaxin-1 and vesicle-associated membrane protein (VAMP) could contribute to enhanced complex function. To investigate these pathways, we first identified a 15-kDa SNAP25 fragment (f-S25) in human and rat brains, highly enriched in synaptosomal extractions, and mainly attached to cytosolic membranes with low hydrophobicity. The presence of f-S25 is consistent with reports of calpain-mediated SNAP25 cleavage. Co-immunoprecipitation assays showed that f-S25 retains the ability to bind syntaxin-1, which might prevent VAMP and/or Munc18-1 assembly into the complex. Quantitative analyses in postmortem human orbitofrontal cortex (OFC) revealed that schizophrenia (n = 35), but not major depression (n = 15), is associated with lower amounts of f-S25 (-37%, P = 0.027), and greater SNARE protein-protein interactions (35%, P < 0.001), compared with healthy matched controls (n = 28). Enhanced SNARE complex formation was strongly correlated with lower SNAP25 fragmentation rates (R = 0.563, P < 0.001). Statistical mediation analyses supported the hypothesis that reduced f-S25 density could upregulate SNARE fusion events in schizophrenia. Cortical calpain activity in schizophrenia did not differ from controls. f-S25 levels did not correlate with total calpain activity, indicating that if present, schizophrenia-related calpain dysfunction might occur locally at the presynaptic terminals. Overall, the present findings suggest the existence of an endogenous SNARE complex inhibitor related to SNAP25 proteolysis, associated with enhanced SNARE activity in schizophrenia.Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

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