Abstract
SummaryGABAergic synapses in brain circuits generate inhibitory output signals with submillisecond latency and temporal precision. Whether the molecular identity of the release sensor contributes to these signaling properties remains unclear. Here, we examined the Ca2+ sensor of exocytosis at GABAergic basket cell (BC) to Purkinje cell (PC) synapses in cerebellum. Immunolabeling suggested that BC terminals selectively expressed synaptotagmin 2 (Syt2), whereas synaptotagmin 1 (Syt1) was enriched in excitatory terminals. Genetic elimination of Syt2 reduced action potential-evoked release to ∼10%, identifying Syt2 as the major Ca2+ sensor at BC-PC synapses. Differential adenovirus-mediated rescue revealed that Syt2 triggered release with shorter latency and higher temporal precision and mediated faster vesicle pool replenishment than Syt1. Furthermore, deletion of Syt2 severely reduced and delayed disynaptic inhibition following parallel fiber stimulation. Thus, the selective use of Syt2 as release sensor at BC-PC synapses ensures fast and efficient feedforward inhibition in cerebellar microcircuits.
Highlights
The molecular identity of the Ca2+ sensor at GABAergic synapses has not been determined yet
Differential Expression of synaptotagmin 1 (Syt1) and synaptotagmin 2 (Syt2) between Excitatory and Inhibitory Presynaptic Terminals in Cerebellum Previous expression analysis showed that several synaptotagmin isoforms are expressed in the cerebellum, with strongest expression of Syt1 and Syt2 (Mittelsteadt et al, 2009)
Syt1 immunoreactivity was abundant in both the granule cell layer and the molecular layer, putative presynaptic basket cell (BC) terminals surrounding Purkinje cell (PC) somata were completely devoid of fluorescent labeling (Figures 1A and 1B)
Summary
The molecular identity of the Ca2+ sensor at GABAergic synapses has not been determined yet. The mammalian genome encodes 16 synaptotagmins, eight of which bind Ca2+ (Syt , and 10; Chapman, 2002; Su€dhof, 2002), and three of which act as fast release sensors (Syt, Syt, and Syt; Xu et al, 2007; Kochubey et al, 2016). Which of these synaptotagmins are involved in transmitter release at GABAergic synapses remains unclear. Genetic elimination of Syt reduced release at output synapses of fast-spiking, parvalbumin-expressing interneurons in the hippocampus to $50% of control value (Kerr et al, 2008), suggesting that multiple synaptotagmins, possibly Syt and Syt, work in concert
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