Abstract
One of the most studied central synapses which have provided fundamental insights into cellular mechanisms of neural connectivity is the “giant” excitatory connection between hippocampal mossy fibers (MFs) and CA3 pyramidal cells. Its large presynaptic bouton features multiple release sites and is densely packed with thousands of synaptic vesicles, to sustain a highly facilitating “detonator” transmission. However, whether glutamate release sites at this synapse act independently, in a stochastic manner, or rather synchronously, remains poorly understood. This knowledge is critical for a better understanding of mechanisms underpinning presynaptic plasticity and postsynaptic signal integration rules. Here, we use the optical glutamate sensor SF-iGluSnFR and the intracellular Ca2+ indicator Cal-590 to monitor spike-evoked glutamate release and presynaptic calcium entry in MF boutons. Multiplexed imaging reveals that distinct sites in individual MF giant boutons release glutamate in a probabilistic fashion, also showing use-dependent short-term facilitation. The present approach provides novel insights into the basic mechanisms of neurotransmitter release at excitatory synapses.
Highlights
The dentate gyrus is the entry into the hippocampus, with the mossy fibers innervating both CA3 pyramidal cells and stratum-lacunosum interneurons (Acsády et al, 1998)
These distinct postsynaptic cell populations are connected through distinct presynaptic elements: “giant” mossy fiber boutons across and their smaller (2–3 μm) variant synapsing onto the thorny excrescences of CA3 pyramidal cells, and relatively small (0.5–2 μm) en-passant boutons and the filopodial extensions emerging from gMFBs both connecting to interneurons (Chicurel and Harris, 1992; Acsády et al, 1998; Rollenhagen et al, 2007)
Hippocampal MFB connections show prominent facilitation during repetitive activity and are considered strong “detonating” synapses, generating large postsynaptic responses in CA3 pyramidal cells (Vyleta et al, 2016). This function is sustained by specific morphology, as they show multiple active zones per MFB, and thousands of synaptic vesicles densely packed inside (Acsády et al, 1998; Rollenhagen et al, 2007)
Summary
The dentate gyrus is the entry into the hippocampus, with the mossy fibers (axons of granule cells) innervating both CA3 pyramidal cells and stratum-lacunosum interneurons (Acsády et al, 1998). Hippocampal MFB connections show prominent facilitation during repetitive activity and are considered strong “detonating” synapses, generating large postsynaptic responses in CA3 pyramidal cells (Vyleta et al, 2016) This function is sustained by specific morphology, as they show multiple active zones per MFB, and thousands of synaptic vesicles densely packed inside (Acsády et al, 1998; Rollenhagen et al, 2007). They have been widely studied because MF synapses play a key role in processing spatial information such as pattern completion, pattern separation and storage of sequences of events (Kobayashi and Poo, 2004; Bischofberger et al, 2006). In one gMFB, there were up to four distinct release sites with the first AP inducing glutamate release in only 2 of them and spontaneous release in one of them, independent from the other 3 (Figure 2B)
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