title: A dominant mutation in Snap25 causes impaired vesicle trafficking, sensorimotor gating, and ataxia in the blind-drunk mouse.
abstract: The neuronal soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex is essential for synaptic vesicle exocytosis, but its study has been limited by the neonatal lethality of murine SNARE knockouts. Here, we describe a viable mouse line carrying a mutation in the b-isoform of neuronal SNARE synaptosomal-associated protein of 25 kDa (SNAP-25). The causative I67T missense mutation results in increased binding affinities within the SNARE complex, impaired exocytotic vesicle recycling and granule exocytosis in pancreatic beta-cells, and a reduction in the amplitude of evoked cortical excitatory postsynaptic potentials. The mice also display ataxia and impaired sensorimotor gating, a phenotype which has been associated with psychiatric disorders in humans. These studies therefore provide insights into the role of the SNARE complex in both diabetes and psychiatric disease.
authors.affiliation: Medical Research Council Functional Genetics Unit, University of Oxford, South Parks Road, Oxford, OX1 3QX, United Kingdom.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Jeans
authors.forename: Peter L
authors.initials: PL
authors.lastname: Oliver
authors.forename: Reuben
authors.initials: R
authors.lastname: Johnson
authors.forename: Marco
authors.initials: M
authors.lastname: Capogna
authors.forename: Jenny
authors.initials: J
authors.lastname: Vikman
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Molnár
authors.forename: Arran
authors.initials: A
authors.lastname: Babbs
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Partridge
authors.forename: Albert
authors.initials: A
authors.lastname: Salehi
authors.forename: Martin
authors.initials: M
authors.lastname: Bengtsson
authors.forename: Lena
authors.initials: L
authors.lastname: Eliasson
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
authors.forename: Kay E
authors.initials: KE
authors.lastname: Davies
mesh_terms: D000435:Alcoholic Intoxication; D000818:Animals; D001259:Ataxia / Q000235:genetics*; D003920:Diabetes Mellitus / Q000209:etiology; D005089:Exocytosis / Q000235:genetics*; D020233:Gait Disorders, Neurologic / Q000235:genetics*; D005799:Genes, Dominant; D050417:Insulin-Secreting Cells; D001523:Mental Disorders / Q000209:etiology; D051379:Mice; D008817:Mice, Mutant Strains; D023421:Models, Animal; D020125:Mutation, Missense; D050600:SNARE Proteins / Q000502:physiology; D013572:Synaptic Vesicles / Q000235:genetics*; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics* / Q000502:physiology
chemical_list: D050600:SNARE Proteins; D050825:Synaptosomal-Associated Protein 25