Vesicular Zinc Regulates the Ca²⁺Sensitivity of a Subpopulation of Presynaptic Vesicles at Hippocampal Mossy Fiber Terminals

Abstract

Synaptic vesicles segregate into functionally diverse subpopulations within presynaptic terminals, yet there is no information about how this may occur. Here we demonstrate that a distinct subgroup of vesicles within individual glutamatergic, mossy fiber terminals contain vesicular zinc that is critical for the rapid release of a subgroup of synaptic vesicles during increased activity in mice. In particular, vesicular zinc dictates the Ca 2ϩ sensitivity of release during high-frequency firing. Intense synaptic activity alters the subcellular distribution of zinc in presynaptic terminals and decreases the number of zinc-containing vesicles. Zinc staining also appears in endosomes, an observation that is consistent with the preferential replenishment of zinc-enriched vesicles by bulk endocytosis. We propose that functionally diverse vesicle pools with unique membrane protein composition support different modes of transmission and are generated via distinct recycling pathways.

AMPA receptor inhibition by synaptically released zinc

“…These results suggest that zinc-containing vesicles may form a functionally and/or anatomically distinct population. This hypothesis is consistent with previous studies showing that ZnT3 interacts with the adaptor protein AP3 and is preferentially targeted to a distinct vesicle subpopulation (39,40). The anatomical and functional properties of different zinc-containing synapses and the relative distribution and release dynamics of zinc-containing vesicles may determine the requirement for differential activity patterns capable of eliciting zinc modulation of AMPAR EPSCs in zinc-containing glutamatergic synapses.…”

Synaptic Zn2+Inhibits Neurotransmitter Release by Promoting Endocannabinoid Synthesis

“…The requirement for trains of presynaptic action potentials is consistent with the recent proposal that Zn 2+ -containing synaptic mossy fiber vesicles populate the reserve -- not the readily released -- pool (Lavoie et al, 2011). Although the detailed physiological conditions leading to mZnR-mediated signaling remain undetermined, our findings suggest that, in response to a brief 30 Hz train, endogenous Zn 2+ levels set the threshold for eliciting short-term plasticity (Fig.…”

“…These studies have revealed that synaptic Zn 2+ -- as an allosteric modulator -- inhibits GABA A , NMDA, and kainate receptors (Paoletti et al, 1997; Vogt et al, 2000; Ruiz et al, 2004; Mott et al, 2008; Nozaki et al, 2011; Veran et al, 2012), while potentiating glycine receptors (Hirzel et al, 2006). Moreover, synaptic Zn 2+ -- as a trigger of signaling pathways -- is thought to be required for mossy fiber long-term potentiation (LTP) via pre– and postsynaptic mechanisms (Huang et al, 2008; Pan et al, 2011); however, these results are not consistent with other studies suggesting that Zn 2+ signaling does not affect mossy fiber LTP (Vogt et al, 2000; Lavoie et al, 2011). Indeed, the establishment of specific pre- or postsynaptic pathways of Zn 2+ -mediated signaling and their physiological role on neuronal processing remain poorly understood.…”

SNARE-dependent upregulation of potassium chloride co-transporter 2 activity after metabotropic zinc receptor activation in rat cortical neurons in vitro

“…As such, possible anticonvulsant actions of the metal have been noted (Fukahori and Itoh, 1990, Elsas et al, 2009). Vesicular Zn 2+ has also been shown to regulate the Ca 2+ sensitivity of release at high firing frequencies (Lavoie et al, 2011). Zinc can modify excitability by allosterically modulating both excitatory and inhibitory neurotransmitter receptors (Hosie et al, 2003, Rachline et al, 2005, Paoletti et al, 2009, Sensi et al, 2009).…”