Synaptotagmin-2 Is Essential for Survival and Contributes to Ca²⁺ Triggering of Neurotransmitter Release in Central and Neuromuscular Synapses

Biochemical and genetic data suggest that synaptotagmin-2 functions as a Ca²⁺ sensor for fast neurotransmitter release in caudal brain regions, but animals and/or synapses lacking synaptotagmin-2 have not been examined. We have now generated mice in which the 5’ end of the synaptotagmin-2 gene was replaced by lacZ. Using β-galactosidase as a marker, we show that, consistent with previous studies, synaptotagmin-2 is widely expressed in spinal cord, brainstem, and cerebellum, but is additionally present in selected forebrain neurons, including most striatal neurons and some hypothalamic, cortical, and hippocampal neurons. Synaptotagmin-2-deficient mice were indistinguishable from wild-type littermates at birth, but subsequently developed severe motor dysfunction, and perished at ~3 weeks of age. Electrophysiological studies in cultured striatal neurons revealed that the synaptotagmin-2 deletion slowed the kinetics of evoked neurotransmitter release without altering the total amount of release. In contrast, synaptotagmin-2-deficient neuromuscular junctions (NMJs) suffered from a large reduction in evoked release and changes in short-term synaptic plasticity. Furthermore, in mutant NMJs, the frequency of spontaneous miniature release events was increased both at rest and during stimulus trains. Viewed together, our results demonstrate that the synaptotagmin-2 deficiency causes a lethal impairment in synaptic transmission in selected synapses. This impairment, however, is less severe than that produced in forebrain neurons by deletion of synaptotagmin-1, presumably because at least in NMJs, synaptotagmin-1 is coexpressed with synaptotagmin-2, and both together mediate fast Ca²⁺-triggered release. Thus, synaptotagmin-2 is an essential synaptotagmin isoform that functions in concert with other synaptotagmins in the Ca²⁺ triggering of neurotransmitter release

American Thoracic Society 2019 Pediatric Core Curriculum

The American Thoracic Society Pediatric Core Curriculum updates clinicians annually in pediatric pulmonary disease in a 3 to 4 year recurring cycle of topics. The 2019 course was presented in May during the Annual International Conference. An American Board of Pediatrics Maintenance of Certification module and a continuing medical education exercise covering the contents of the Core Curriculum can be accessed online at www.thoracic.org.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152541/1/ppul24482_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152541/2/ppul24482.pd

Evolutionary origin of synapses and neurons – Bridging the gap

The evolutionary origin of synapses and neurons is an enigmatic subject that inspires much debate. Non-bilaterian metazoans, both with and without neurons and their closest relatives already contain many components of the molecular toolkits for synapse functions. The origin of these components and their assembly into ancient synaptic signaling machineries are particularly important in light of recent findings on the phylogeny of non-bilaterian metazoans. The evolution of synapses and neurons are often discussed only from a metazoan perspective leaving a considerable gap in our understanding. By taking an integrative approach we highlight the need to consider different, but extremely relevant phyla and to include the closest unicellular relatives of metazoans, the ichthyosporeans, filastereans and choanoflagellates, to fully understand the evolutionary origin of synapses and neurons. This approach allows for a detailed understanding of when and how the first pre- and postsynaptic signaling machineries evolved

Evolutionary origin of synapses and neurons - Bridging the gap

The evolutionary origin of synapses and neurons is an enigmatic subject that inspires much debate. Non-bilaterian metazoans, both with and without neurons and their closest relatives already contain many components of the molecular toolkits for synapse functions. The origin of these components and their assembly into ancient synaptic signaling machineries are particularly important in light of recent findings on the phylogeny of non-bilaterian metazoans. The evolution of synapses and neurons are often discussed only from a metazoan perspective leaving a considerable gap in our understanding. By taking an integrative approach we highlight the need to consider different, but extremely relevant phyla and to include the closest unicellular relatives of metazoans, the ichthyosporeans, filastereans and choanoflagellates, to fully understand the evolutionary origin of synapses and neurons. This approach allows for a detailed understanding of when and how the first pre- and postsynaptic signaling machineries evolved

Synaptotagmin-2 Controls Regulated Exocytosis but Not Other Secretory Responses of Mast Cells*

Mast cell degranulation is a highly regulated, calcium-dependent process, which is important for the acute release of inflammatory mediators during the course of many pathological conditions. We previously found that Synaptotagmin-2, a calcium sensor in neuronal exocytosis, was expressed in a mast cell line. We postulated that this protein may be involved in the control of mast cell-regulated exocytosis, and we generated Synaptotagmin-2 knock-out mice to test our hypothesis. Mast cells from this mutant animal conferred an abnormally decreased passive cutaneous anaphylaxis reaction on mast cell-deficient mice that correlated with a specific defect in mast cell-regulated exocytosis, leaving constitutive exocytosis and nonexocytic mast cell effector responses intact. This defect was not secondary to abnormalities in the development, maturation, migration, morphology, synthesis, and storage of inflammatory mediators, or intracellular calcium transients of the mast cells. Unlike neurons, the lack of Synaptotagmin-2 in mast cells was not associated with increased spontaneous exocytosis