Dynamic partitioning of synaptic vesicle pools by the snare-binding protein tomosyn

Victor A. Cazares, Meredith M. Njus, Amanda Manly, Johnny J. Saldate, Arasakumar Subramani, Yoav Ben-Simon, Michael A. Sutton, Uri Ashery, Edward L. Stuenkel

Research output: Contribution to journalArticlepeer-review


Neural networks engaged in high-frequency activity rely on sustained synaptic vesicle recycling and coordinated recruitment from functionally distinct synaptic vesicle (SV) pools. However, the molecular pathways matching neural activity to SV dynamics and release requirements remain unclear. Here we identify unique roles of SNARE-binding Tomosyn1 (Tomo1) proteins as activity-dependent substrates that regulate dynamics of SV pool partitioning at rat hippocampal synapses. Our analysis is based on monitoring changes in distinct functionally defined SV pools via V-Glut1-pHluorin fluorescence in cultured hippocampal neurons in response to alterations in presynaptic protein expression. Specifically, we find knockdown of Tomo1 facilitates release efficacy from the Readily Releasable Pool (RRP), and regulates SV distribution to the Total Recycling Pool (TRP), which is matched by a decrease in the SV Resting Pool. Notably, these effects were reversed by Tomo1 rescue and overexpression. Further, we identify that these actions of Tomo1 are regulated via activity-dependent phosphorylation by cyclin-dependent kinase 5 (Cdk5). Assessment of molecular interactions that may contribute to these actions identified Tomo1 interaction with the GTP-bound state of Rab3A, an SV GTPase involved in SV targeting and presynaptic membrane tethering. In addition, Tomo1 via Rab3A-GTP was also observed to interact with Synapsin 1a/b cytoskeletal interacting proteins. Finally, our data indicate thatTomo1regulation ofSVpool sizes serves to adapt presynaptic neurotransmitter release to chronic silencing of network activity. Overall, the results establish Tomo1 proteins as central mediators in neural activity-dependent changes in SV distribution among SV pools.

Original languageEnglish
Pages (from-to)11208-11222
Number of pages15
JournalJournal of Neuroscience
Issue number44
StatePublished - 2 Nov 2016


  • Cdk5
  • Hippocampal neuron
  • Neurotransmitter release
  • Plasticity
  • Synaptic vesicle
  • Tomosyn


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