Influence of Synaptic Vesicle Position on Release Probability and Exocytotic Fusion Mode

Park, Hyokeun; Li, Yulong; Tsien, Richard W.

doi:10.1126/science.1216937

Cited by 114 publications

(184 citation statements)

References 43 publications

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“…However, we find greater NMDAR activation at MVR than UVR synapses, excluding synapses with high rates of asynchrony. In addition, FF release is reported to be evenly distributed across the active zone while KR is located more centrally (Park et al, 2012); thus more glutamate would be released nearer the periphery at FF synapses than at KR-to-FF synapses and would lead to larger NMDAR currents, again contrary to our data. Though KR may well occur at PF synapses, we would suggest that, by itself, a KR-to-FF transient cannot account for our results.…”

Section: Distinct Populations Of Pf Terminalscontrasting

confidence: 99%

Activation of Extrasynaptic NMDARs at Individual Parallel Fiber–Molecular Layer Interneuron Synapses in Cerebellum

Nahir

Jahr

2013

J. Neurosci.

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NMDA receptors (NMDARs) expressed by cerebellar molecular layer interneurons (MLIs) are not activated by single exocytotic events but can respond to glutamate spillover following coactivation of adjacent parallel fibers (PFs), indicating that NMDARs are perisynaptic. Several types of synaptic plasticity rely on these receptors but whether they are activated at isolated synapses is not known. Using a combination of electrophysiological and optical recording techniques in acute slices of rat cerebellum, along with modeling, we find that repetitive activation of single PF-MLI synapses can activate NMDARs in MLIs. High-frequency stimulation, multivesicular release (MVR), or asynchronous release can each activate NMDARs. Frequency facilitation was found at all PF-MLI synapses but, while some showed robust MVR with increased release probability, most were limited to univesicular release. Together, these results reveal a functional diversity of PF synapses, which use different mechanisms to activate NMDARs.

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Section: Distinct Populations Of Pf Terminalscontrasting

confidence: 99%

Activation of Extrasynaptic NMDARs at Individual Parallel Fiber–Molecular Layer Interneuron Synapses in Cerebellum

Nahir

Jahr

2013

J. Neurosci.

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“…S3 shows fast measurements). Of importance, given that membrane retrieval in KO terminals was affected only mildly, our observations here differ from kiss-and-run type exocytosis (30). In addition, WT and KO terminals responded similarly to perturbation of AP2 by dialysis of a Synaptotagmin 2 (Syt2) 2-derived AP2-binding peptide (9), resulting in nearly complete elimination of membrane retrieval and of SV replenishment in both genotypes (Fig.…”

Section: Resultsmentioning

confidence: 65%

Fast neurotransmitter release regulated by the endocytic scaffold intersectin

Sakaba

Kononenko

Bacetic

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Sustained fast neurotransmission requires the rapid replenishment of release-ready synaptic vesicles (SVs) at presynaptic active zones. Although the machineries for exocytic fusion and for subsequent endocytic membrane retrieval have been well characterized, little is known about the mechanisms underlying the rapid recruitment of SVs to release sites. Here we show that the Down syndromeassociated endocytic scaffold protein intersectin 1 is a crucial factor for the recruitment of release-ready SVs. Genetic deletion of intersectin 1 expression or acute interference with intersectin function inhibited the replenishment of release-ready vesicles, resulting in short-term depression, without significantly affecting the rate of endocytic membrane retrieval. Acute perturbation experiments suggest that intersectin-mediated vesicle replenishment involves the association of intersectin with the fissioning enzyme dynamin and with the actin regulatory GTPase CDC42. Our data indicate a role for the endocytic scaffold intersectin in fast neurotransmitter release, which may be of prime importance for information processing in the brain.endocytosis | synaptic transmission | synaptic vesicle recruitment N eurotransmission depends on the exocytosis of synaptic vesicles (SVs) at active zones (AZs) and the subsequent retrieval of SV membranes by endocytosis. Sustained fast neurotransmission requires rapid replenishment of release-ready SVs composing the readily releasable pool (RRP) (1-3). Whereas the machinery for SV fusion is well understood, the mechanisms controlling the number of SVs within the RRP and the rate of replenishment remain enigmatic (4, 5). It has been postulated that the rate of replenishment of release-ready SVs in addition to molecular priming reactions is regulated by the availability of SV release sites (6-8). The reuse of release sites appears to depend on components of the endocytic machinery, including dynamin (9-12). However, considering that the rate of endocytosis is ∼10-100 times slower than that of replenishment of release-ready SVs, the question arises as to how endocytic proteins affect rapid neurotransmitter release.Data from dynamin mutants can be interpreted as a deficit in SV recycling (e.g., loss of the SV reserve pool; ref. 13). Alternatively, endocytic proteins may regulate exocytosis more directly, independent of membrane retrieval. If so, interference with select endocytic factors might impair replenishment of release-ready SVs without affecting the rate of SV membrane retrieval.A possible candidate for such regulation is the early-acting multidomain endocytic protein intersectin (14-18), a protein overexpressed in Down syndrome, which also associates with components of the exocytic machinery [i.e., synaptosomal-associated protein 25 (SNAP-25)] (19). Although a role for intersectin in endocytosis has been established in Drosophila (16,17), the precise function of intersectin 1 in mammalian central synapses has not yet been analyzed extensively. Optical measurements of endocytosis in cultured ...

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“…The estimated recovery is 20% smaller at the end of fast recovery and 25% smaller at 6 min during slow recovery (Fig. 5P), suggesting that both phases of recovery are under the influence of additional factors (16,24,31,32). However, although these additional factors appear to be involved in the control of RRP recovery rates for fast and slow pathways (Fig.…”

Section: Distinct Roles Of Dynamin Isoforms During Low-frequency Apmentioning

confidence: 92%

Dynamin Isoforms Decode Action Potential Firing for Synaptic Vesicle Recycling

Tanifuji

Funakoshi‐Tago

Ueda

et al. 2013

Journal of Biological Chemistry

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Background: The molecular mechanism linking variation in presynaptic neuronal activity to vesicle trafficking is unknown. Results: Three isoforms of dynamin, an essential endocytic protein, mediate vesicle reuse, having distinct rate and time constants with physiological action potential frequencies. Conclusion: Dynamin isoforms select appropriate vesicle reuse pathways associated with specific neuronal firing patterns. Significance: Individual dynamin isoforms regulate distinct synaptic vesicle reuse pathways that cover the full range of physiological action potential frequencies.

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Influence of Synaptic Vesicle Position on Release Probability and Exocytotic Fusion Mode

Cited by 114 publications

References 43 publications

Activation of Extrasynaptic NMDARs at Individual Parallel Fiber–Molecular Layer Interneuron Synapses in Cerebellum

Activation of Extrasynaptic NMDARs at Individual Parallel Fiber–Molecular Layer Interneuron Synapses in Cerebellum

Fast neurotransmitter release regulated by the endocytic scaffold intersectin

Dynamin Isoforms Decode Action Potential Firing for Synaptic Vesicle Recycling

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