Cycle 2 project 6

Project 6: High resolution imaging of ‘‘Positional Priming’’


PhD student: Girish Kedar, India
Home Institute:
Amsterdam Neuroscience; Principle Investigator: Heidi de Wit
Host Institute: European Neuroscience Institute Göttingen; Principle Investigator: Silvio Rizzoli / Erwin Neher

Executive Summary
Since the work of Katz in the early 1950s it has been known that Ca2+ -entry is coupled within milliseconds to a secretory event[i]. Rapid neurotransmitter release in synchrony with Ca2+- entry   requires an exquisite ultrastructural organization that allows interactions between Ca2+- channels and release-ready-vesicles (RRP) at shortest possible distances1 . It has been demonstrated that this secretory vesicle (SG-)positioning to Ca2+-channels, also termed ‘‘positional priming’’, is important for synchronous-release[ii],[iii],[iv]. Although it has been hypothesized that ‘‘positional priming’’ requires In electron micrographs, many neurotransmitter-containing vesicles ‘dock’ at the target membrane (see figure).

Docking is the first necessary step in the secretory pathway to gain fusion competence[v] and it seems that during Ca2+-entry RRP size corresponds with the number of docking vesicles[vi], whereas only a fraction of the docked vesicles can be primed[vii]. For many years the molecular docking machinery was unknown. The applicant resolved the minimal docking machinery in neuroendocrine cells using electron-microscopic (EM)-analyses8. The importance of these docking-proteins is illustrated by the fact that they are strongly linked to brain-disorders, in particular neurodegenerative-diseases and mental-illnesses, and also associate with intelligence. Currently, it is unclear how these docking-proteins regulate positional priming. In addition, primed vesicles can be sub-divided in different classes of release-readiness, reluctantly releasing and rapidly releasing depending on their positioning to Ca2+-channels4 .

Our aim is to reveal the relationship between docking phenotypes and altered positional priming. This study will help to understand neurological-disorders linked to these docking genes as well as   failures of positional priming in the human brain.

Figure. Morphological docking phenotypes & positional priming in chromaffin cells and synapses.
Schematic representation of morphological docked (top) and undocked (bottom) secretory granules (SGs; left panel) and synaptic vesicles (SVs; right panel). Middle panel: EM-pictures of chromaffin cells (left) and hippocampal synapses (right) showing many morphological docked SGs(left)/SVs(right) in control (top) but many undocked Gs(left)/SVs(right) in mutants (bottom). See 8. for details.

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