Synapsin Selectively Controls the Mobility of Resting Pool Vesicles at Hippocampal Terminals

Abstract

Presynaptic terminals are specialized sites for information transmission where vesicles fuse with the plasma membrane and are locally recycled. Recent work has extended this classical view, with the observation that a subset of functional vesicles is dynamically shared between adjacent terminals by lateral axonal transport. Conceptually, such transport would be expected to disrupt vesicle retention around the active zone, yet terminals are characterized by a high-density vesicle cluster, suggesting that counteracting stabilizing mechanisms must operate against this tendency. The synapsins are a family of proteins that associate with synaptic vesicles and determine vesicle numbers at the terminal, but their specific function remains controversial. Here, using multiple quantitative fluorescencebased approaches and electron microscopy, we show that synapsin is instrumental for resisting vesicle dispersion and serves as a regulatory element for controlling lateral vesicle sharing between synapses. Deleting synapsin disrupts the organization of presynaptic vesicle clusters, making their boundaries hard to define. Concurrently, the fraction of vesicles amenable to transport is increased, and more vesicles are translocated to the axon. Importantly, in neurons from synapsin knock-out mice the resting and recycling pools are equally mobile. Synapsin, when present, specifically restricts the mobility of resting pool vesicles without affecting the division of vesicles between these pools. Specific expression of synapsin IIa, the sole isoform affecting synaptic depression, rescues the knock-out phenotype. Together, our results show that synapsin is pivotal for maintaining synaptic vesicle cluster integrity and that it contributes to the regulated sharing of vesicles between terminals.

Munc18-1 redistributes in nerve terminals in an activity- and PKC-dependent manner

“…Munc18-1-Venus exchange is best described with a fast ( = 4.6 s) and a slow component ( = 60 s), comparable to syntaxin-1 (Ribrault et al, 2011), whereas Bassoon (Tsuriel et al, 2009;Schröder et al, 2013), Munc13-1 (Kalla et al, 2006), liprin-2 (Spangler et al, 2013), and synapsin-1 (Tsuriel et al, 2006) turnover at synapses is much slower, with exchange rates in the order of minutes to hours. Exchange rates of the total synaptic vesicle pool are even slower (Orenbuch et al, 2012b), although individual synaptic vesicle exchange between boutons is relatively fast (Darcy et al, 2006;Staras et al, 2010;Herzog et al, 2011). Synaptic activity increased the mobility of Munc18-1-Venus and Stx-YFP (Fig.…”

Intellectual disability and autism spectrum disorders: Causal genes and molecular mechanisms

“…presynaptic compartments. It was noted that in the absence of Syns, SVs show higher mobility and become dispersed along axons (Fornasiero et al, 2012; Orenbuch et al, 2012). Lack of Syn1 and/or Syn11 triggers a strong epileptic phenotype in mice associated with cognitive impairments (Greco et al, 2013).…”

Synapsins Contribute to the Dynamic Spatial Organization of Synaptic Vesicles in an Activity-Dependent Manner

“…Our work, together with a recently published paper (Orenbuch et al, 2012), are the first to directly address the redistribution of SVs at synaptic boutons and in the rest of the axon in the absence of Syns. Strikingly, both works establish that Syns are essential to shape presynaptic terminals, by maintaining compact SV clusters and by restricting SVs at the terminal.…”

“…As suggested by Orenbuch et al (2012), it is possible that the ratio of the recycling pool of SVs with respect to total SVs is regulated in a Syn-independent manner, because in their experiments WT and TKO terminals exchange the same fraction of recycling vesicles. However, it should be noted that those measurements were performed on neurons loaded with FM1-43 [N-(3-triethylammoniumpropyl)-4-(4-(dibutylamino)styryl) pyridinium dibromide] by exposure to a hyperkalemic medium, i.e., a stimulation that does not reproduce what happens in physiological conditions.…”