![]() While SVs are loaded with their content directly at synapses, where they subsequently fuse with the presynaptic membrane, DCVs are formed in neuronal somas at the trans-Golgi network (TGN), from where they travel to the release sites that are not confined to synapses. SV and DCV substantially differ in their morphology and mechanisms of formation (reviewed in De Camilli and Jahn, 1990 Gondré-Lewis et al., 2012). glutamate, γ-aminobutyric acid) are released from SVs, whereas neuropeptides and neurotrophic factors are packaged in and secreted from DCVs. Classical small-molecule neurotransmitters (e.g. Editor's evaluationīrain activity relies on the precisely regulated secretion of different chemical messengers, and most neurons co-release multiple neurotransmitters ( Nusbaum et al., 2017). Taken together, our findings argue against an inhibitory role of tomosyns in neuronal DCV exocytosis and suggests an evolutionary conserved function of tomosyns in the packaging of secretory cargo at the Golgi. ![]() Additionally, tomosyn-deficient neurons showed impaired mRNA expression of some DCV cargos, which was not restored by re-expression of tomosyn and was also observed in Cre-expressing wild-type neurons not carrying lox P sites, suggesting a direct effect of Cre recombinase on neuronal transcription. The size of the trans-Golgi network and DCVs was decreased, and the speed of DCV cargo flux through Golgi was increased in tomosyn-deficient neurons, suggesting a role for tomosyns in DCV biogenesis. Tomosyn’s SNARE domain was dispensable for the rescue. BDNF levels were largely restored by re-expression of tomosyn but not by inhibition of lysosomal proteolysis. Surprisingly, loss of tomosyns did not affect the number of DCV fusion events but resulted in a strong reduction of intracellular levels of DCV cargos, such as neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF). We monitored DCV exocytosis at single vesicle resolution in tomosyn-deficient primary neurons using a validated pHluorin-based assay. ![]() Here, we addressed this question using a new mouse model with a conditional deletion of tomosyn ( Stxbp5) and its paralogue tomosyn-2 ( Stxbp5l). In the brain, tomosyn inhibits the fusion of synaptic vesicles (SVs), whereas its role in the fusion of neuropeptide-containing dense core vesicles (DCVs) is unknown. Tomosyn is a large, non-canonical SNARE protein proposed to act as an inhibitor of SNARE complex formation in the exocytosis of secretory vesicles.
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