Cycle 4 project 3

Mapping the synaptic gene networks governing tomosyn-dependent regulation of neurotransmission


Bourgeois-QuentinPhD student: Quentin Bourgeois, France
Home Institute: Amsterdam Neuroscience; Principle Investigator: Sander Groffen
Host Institute: European Neuroscience Institute Göttingen; Principle Investigator: J.S. Rhee

Executive Summary

The secretory strength of synapses in the brain is continuously adapted to establish memory traces and maintain network stability under a wide range of environmental conditions. Synaptic dysregulation is observed in many brain disorders, also referred to as synaptopathies, including schizophrenia, autism, major depression disorder, movement disorders and epilepsy. A key step in synaptic release is the assembly of syntaxin, SNAP25 and synaptobrevin into the SNARE complex, an event that is regulated by a number of accessory proteins which cause synaptic defects and reduced viability upon genetic ablation. Our current knowledge of the signaling cascades that converge upon SNARE-accessory proteins is insufficient to understand the etiology of even the most important synaptopathies. Thus, a better description of the involved gene networks and signaling molecules will provide valuable information to complement human gene identification studies.

Here we focus on tomosyn, a protein that interacts with syntaxin and SNAP25 to inhibit synaptic release and neurite outgrowth. Tomosyn is conserved from yeast to humans. Inhibition by tomosyn is dependent on several important pathways including Ca2+-, cAMP-dependent, Rho kinase and SUMOylation pathways. In contrast to worms and flies, mammals encode two distinct tomosyn genes, which are both alternatively spliced to produce at least seven isoforms in total. Tomosyn-2 was originally cloned by the applicant and conditional and classical knock-out mice are now available (unpublished work). Homozygous tomosyn-2 null mice have a reduced survival at three weeks of age and exhibit an increased EPSC amplitude. This phenotype is reminiscent of that of tomosyn-1 null mice that have a reduced viability and a higher EPSC amplitude in mossy fiber synapses. The similar phenotypes, together with overlapping expression patterns and high sequence similarity suggest that tomosyn-1 and -2 are functionally redundant.


This study will provide detailed information about how tomosyn inhibits synaptic strength and which upstream signaling mechanisms govern tomosyn activity. For this purpose we identify three subprojects:

  • Test functional redundancy of tomosyn-1 and -2 and establish a model system of mammalian CNS synapses that completely lack tomosyn activity.
  • Identify tomosyn interactors that contribute to synaptic regulation.
  • Identify the order of events in the identified pathways.
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