Selective reduction in synaptic proteins involved in vesicle docking and signalling at synapses in the ataxic mutant mouse stargazer.
The spontaneous recessive mutant mouse stargazer has a specific and pronounced deficit in brain-derived neurotrophic factor (BDNF) mRNA expression in the cerebellum. Cerebellar granule cells, in particular, show a selective and near-total loss of BDNF. The mutation involves a defect in the calcium channel subunit Cacng2. This severely reduces expression of stargazin. A stargazin-induced failure in BDNF expression is thought to underlie the cerebellar ataxia with which the mutant presents. BDNF is known to regulate plasticity at cerebellar synapses. However, relatively little is known about the mechanism involved. We previously demonstrated that the stargazer mutation affects the phenotype of cerebellar glutamatergic neurons. Stargazer neurons have less glutamate and proportionally fewer docked vesicles at presynaptic sites than controls. In the current study, we investigate the mechanism underlying BDNF-induced synaptic changes by analyzing alterations in synaptic signalling proteins in the stargazer cerebellum. Expression levels of synaptic proteins were evaluated by measuring relative density of immunogold label over granule cell terminals in ultrathin sections from ataxic stargazer mutants compared with matched nonataxic littermates. We show that there is a selective and marked depletion in the levels of vesicle-associated proteins (synaptobrevin, synaptophysin, synaptotagmin, and Rab3a) but not of plasma membrane-associated protein (SNAP-25) in the terminals of the BDNF-deficient granule cells. Changes are restricted to the cerebellum; levels in the hippocampus are unaltered. These data suggest that the BDNF deficits in the cerebellum of stargazer affect synaptic vesicle docking by selectively altering synaptic-protein distribution and abundance.
Leitch
Beulah
B
Department of Anatomy and Structural Biology, Otago School of Medical Sciences, University of Otago, Dunedin, 9054 New Zealand. beulah.leitch@stonebow.otago.ac.nz
Shevtsova
Olga
O
Kerr
John Richard
JR
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002531:Cerebellum / Q000033:anatomy & histology / Q000737:chemistry; D005260:Female; D006624:Hippocampus / Q000033:anatomy & histology / Q000737:chemistry; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D050683:R-SNARE Proteins / Q000032:analysis; D050600:SNARE Proteins / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000737:chemistry* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D016708:Synaptophysin / Q000032:analysis; D050825:Synaptosomal-Associated Protein 25 / Q000032:analysis
D019208:Brain-Derived Neurotrophic Factor; D050683:R-SNARE Proteins; D050600:SNARE Proteins; D016708:Synaptophysin; D050825:Synaptosomal-Associated Protein 25