Vesicular Glutamate Transporter Expression Ensures High-Fidelity Synaptic Transmission at the Calyx of Held Synapses

• Published in: Cell reports (Cambridge) 2020-08, Vol.32 (7), p.108040-108040, Article 108040
• Main Authors: Nakakubo, Yutaro, Abe, Saeka, Yoshida, Tomofumi, Takami, Chihiro, Isa, Masayuki, Wojcik, Sonja M., Brose, Nils, Takamori, Shigeo, Hori, Tetsuya
• Format: Article
• Language: English
• Subjects: Calyx of Held synapse; excitatory transmission; glutamate; neurotransmitter uptake; synaptic vesicles; VGLUT
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108040

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 transmission under certain conditions that entail reduced VGLUT levels during development as well as various neuropathological processes. [Display omitted] •Basal synaptic transmission in VGLUT1-KO calyx of Held synapses is largely intact•VGLUT1 loss slows down SV refilling with glutamate•VGLUT1 loss leads to abnormal synaptic failures during sustained stimulation•The speed of glutamate loading into SVs can be rate limiting for neurotransmission Glutamate loading into synaptic vesicles (SVs) is indispensable for excitatory neurotransmission. Yet it is unclear whether the speed of glutamate loading is rate limiting. Here, Nakakubo et al. report that glutamate loading is slowed down in VGLUT1-KO calyx of Held synapses, which consequently results in abnormal synaptic failures during sustained stimulation.