A dominant mutation in Snap25 causes impaired vesicle trafficking, sensorimotor gating, and ataxia in the blind-drunk mouse.
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.
Jeans
Alexander F
AF
Medical Research Council Functional Genetics Unit, University of Oxford, South Parks Road, Oxford, OX1 3QX, United Kingdom.
Oliver
Peter L
PL
Johnson
Reuben
R
Capogna
Marco
M
Vikman
Jenny
J
Molnár
Zoltán
Z
Babbs
Arran
A
Partridge
Christopher J
CJ
Salehi
Albert
A
Bengtsson
Martin
M
Eliasson
Lena
L
Rorsman
Patrik
P
Davies
Kay E
KE
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
D050600:SNARE Proteins; D050825:Synaptosomal-Associated Protein 25