Abstract
Recycling of synaptic vesicles (SVs) at presynaptic terminals is required for sustained neurotransmitter release. Although SV endocytosis is a rate-limiting step for synaptic transmission, it is unclear whether the rate of the subsequent SV refilling with neurotransmitter also influences synaptic transmission. By analyzing vesicular glutamate transporter 1 (VGLUT1)-deficient calyx of Held synapses, in which both VGLUT1 and VGLUT2 are co-expressed in wild-type situation, we found that VGLUT1 loss causes a drastic reduction in SV refilling rate down to ∼25% of wild-type values, with only subtle changes in basic synaptic parameters. Strikingly, VGLUT1-deficient synapses exhibited abnormal synaptic failures within a few seconds during high-frequency repetitive firing, which was recapitulated by manipulating presynaptic Cl- concentrations to retard SV refilling. Our data show that the speed of SV refilling can be rate limiting for synaptic transmissionunder certain conditions that entail reduced VGLUT levels during development as well as various neuropathological processes.
Highlights
At chemical synapses, neurotransmitters are released from synaptic vesicles (SVs) by exocytosis
Our study demonstrates that deletion of vesicular glutamate transporter 1 (VGLUT1) in calyx of Held synapses causes only subtle alterations in basic synaptic parameters, such as short-term plasticity, but leads to a defined decrease of the rate of glutamate refilling into SVs to $25% compared with wild-type values
We first tested whether deletion of VGLUT1 would alter expression of VGLUT2 at this synapse
Summary
Neurotransmitters are released from synaptic vesicles (SVs) by exocytosis. SVs are regenerated by endocytosis and refilled with neurotransmitter to contribute to subsequent rounds of exocytosis (Su€dhof, 2004). Endocytosis is a rate-limiting step for the maintenance of synaptic transmission at many synapses (e.g., Yamashita et al, 2005), it has so far not been investigated whether the speed of neurotransmitter refilling of SVs contributes to synaptic efficacy. SV refilling cannot be rate limiting for synaptic transmission unless the time it requires exceeds the time needed for SV reuse. Some evidence has emerged to indicate very rapid endocytosis and SV reuse (Chung et al, 2010; Delvendahl et al, 2016; Ertunc et al, 2007; Ikeda and Bekkers, 2009; Watanabe et al, 2013, 2014), which may operate at shorter timescales than SV refilling, with time constants of $15 s for glutamate (Hori and Takahashi, 2012) and $20–50 s for GABA (Egashira et al, 2016; Yamashita et al, 2018). On the basis of these data, it is possible that the SV refilling process limits synaptic efficacy under certain conditions (e.g., during repetitive stimulation)
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