The mechanisms and functions of spontaneous neurotransmitter release

Key Points

  • Synaptic terminals can release neurotransmitter by spontaneous vesicle fusion that is independent of presynaptic action potentials.

  • The traditional view of spontaneous neurotransmitter release suggests that spontaneous events occur randomly in the absence of stimuli owing to low-probability conformational changes in the vesicle fusion machinery.

  • Recent studies have identified key distinctions between the synaptic vesicle fusion machineries that perform spontaneous versus evoked neurotransmitter release.

  • In mammalian hippocampal synapses and at the Drosophila melanogaster neuromuscular junction, spontaneous and evoked neurotransmitter release events show some spatial segregation and activate distinct populations of postsynaptic receptors.

  • Segregation of spontaneous neurotransmission enables selective neuromodulation that is independent of evoked release.

  • In mammalian hippocampal synapses and at the D. melanogaster neuromuscular junction, spontaneous release events activate specific postsynaptic signal transduction cascades that maintain synaptic efficacy or regulate structural plasticity and synaptic development.

  • Novel strategies that selectively target spontaneous release events are needed to address whether spontaneous release can signal independently during ongoing activity in intact neuronal circuits.


Fast synaptic communication in the brain requires synchronous vesicle fusion that is evoked by action potential-induced Ca2+ influx. However, synaptic terminals also release neurotransmitters by spontaneous vesicle fusion, which is independent of presynaptic action potentials. A functional role for spontaneous neurotransmitter release events in the regulation of synaptic plasticity and homeostasis, as well as the regulation of certain behaviours, has been reported. In addition, there is evidence that the presynaptic mechanisms underlying spontaneous release of neurotransmitters and their postsynaptic targets are segregated from those of evoked neurotransmission. These findings challenge current assumptions about neuronal signalling and neurotransmission, as they indicate that spontaneous neurotransmission has an autonomous role in interneuronal communication that is distinct from that of evoked release.

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Figure 1: The earliest recordings of spontaneous synaptic activity.
Figure 2: Three kinetically distinct forms of neurotransmitter release.
Figure 3: Segregation of spontaneous and evoked neurotransmission.
Figure 4: An emerging model of the distributions of vesicular proteins among synaptic vesicle pools.
Figure 5: Postsynaptic signalling pathways that are differentially activated by spontaneous and evoked neurotransmitter release.


  1. 1

    Katz, B. Neural transmitter release: from quantal secretion to exocytosis and beyond. J. Neurocytol. 32, 437–446 (2003).

    CAS  PubMed  Google Scholar 

  2. 2

    Fatt, P. & Katz, B. Spontaneous subthreshold activity at motor nerve endings. J. Physiol. 117, 109–128 (1952).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Fatt, P. & Katz, B. Some observations on biological noise. Nature 166, 597–598 (1950).

    CAS  PubMed  Google Scholar 

  4. 4

    Del Castillo, J. & Katz, B. Quantal components of the end-plate potential. J. Physiol. 124, 560–573 (1954).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Heuser, J. E. & Reese, T. S. Evidence for recycling of synaptic vesicle membrane during transmitter release at the frog neuromuscular junction. J. Cell Biol. 57, 315–344 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Heuser, J. E. et al. Synaptic vesicle exocytosis captured by quick freezing and correlated with quantal transmitter release. J. Cell Biol. 81, 275–300 (1979).

    CAS  Google Scholar 

  7. 7

    Sudhof, T. C. Neurotransmitter release: the last millisecond in the life of a synaptic vesicle. Neuron 80, 675–690 (2013).

    CAS  PubMed  Google Scholar 

  8. 8

    Thesleff, S. Supersensitivity of skeletal muscle produced by botulinum toxin. J. Physiol. 151, 598–607 (1960).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Thesleff, S. Spontaneous transmitter release at the neuromuscular junction. Fundam. Clin. Pharmacol. 2, 89–101 (1988).

    CAS  PubMed  Google Scholar 

  10. 10

    Deitcher, D. L. et al. Distinct requirements for evoked and spontaneous release of neurotransmitter are revealed by mutations in the Drosophila gene neuronal-synaptobrevin. J. Neurosci. 18, 2028–2039 (1998).

    CAS  PubMed  Google Scholar 

  11. 11

    Schoch, S. et al. SNARE function analyzed in synaptobrevin/VAMP knockout mice. Science 294, 1117–1122 (2001).

    CAS  Google Scholar 

  12. 12

    Washbourne, P. et al. Genetic ablation of the t-SNARE SNAP-25 distinguishes mechanisms of neuroexocytosis. Nature Neurosci. 5, 19–26 (2002).

    CAS  PubMed  Google Scholar 

  13. 13

    Bronk, P. et al. Differential effects of SNAP-25 deletion on Ca2+-dependent and Ca2+-independent neurotransmission. J. Neurophysiol. 98, 794–806 (2007).

    CAS  PubMed  Google Scholar 

  14. 14

    Bauerfeind, R., Huttner, W. B., Almers, W. & Augustine, G. J. Quantal neurotransmitter release from early endosomes? Trends Cell Biol. 4, 155–156 (1994).

    CAS  PubMed  Google Scholar 

  15. 15

    Kaeser, P. S. & Regehr, W. G. Molecular mechanisms for synchronous, asynchronous, and spontaneous neurotransmitter release. Annu. Rev. Physiol. 76, 333–363 (2014).

    CAS  PubMed  Google Scholar 

  16. 16

    Angleson, J. K. & Betz, W. J. Intraterminal Ca2+ and spontaneous transmitter release at the frog neuromuscular junction. J. Neurophysiol. 85, 287–294 (2001).

    CAS  PubMed  Google Scholar 

  17. 17

    Sharma, G. & Vijayaraghavan, S. Modulation of presynaptic store calcium induces release of glutamate and postsynaptic firing. Neuron 38, 929–939 (2003).

    CAS  PubMed  Google Scholar 

  18. 18

    Lou, X., Scheuss, V. & Schneggenburger, R. Allosteric modulation of the presynaptic Ca2+ sensor for vesicle fusion. Nature 435, 497–501 (2005).

    CAS  PubMed  Google Scholar 

  19. 19

    Walter, A. M., Pinheiro, P. S., Verhage, M. & Sorensen, J. B. A sequential vesicle pool model with a single release sensor and a Ca2+-dependent priming catalyst effectively explains Ca2+-dependent properties of neurosecretion. PLoS Comput. Biol. 9, e1003362 (2013).

    PubMed  PubMed Central  Google Scholar 

  20. 20

    Kavalali, E. T. et al. Spontaneous neurotransmission: an independent pathway for neuronal signaling? Physiology 26, 45–53 (2011).

    CAS  PubMed  Google Scholar 

  21. 21

    Ramirez, D. M. & Kavalali, E. T. Differential regulation of spontaneous and evoked neurotransmitter release at central synapses. Curr. Opin. Neurobiol. 21, 275–282 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Sudhof, T. C. & Rothman, J. E. Membrane fusion: grappling with SNARE and SM proteins. Science 323, 474–477 (2009).

    PubMed  PubMed Central  Google Scholar 

  23. 23

    Deak, F., Schoch, S., Liu, X., Sudhof, T. C. & Kavalali, E. T. Synaptobrevin is essential for fast synaptic-vesicle endocytosis. Nature Cell Biol. 6, 1102–1108 (2004).

    CAS  PubMed  Google Scholar 

  24. 24

    Takamori, S. et al. Molecular anatomy of a trafficking organelle. Cell 127, 831–846 (2006).

    CAS  Google Scholar 

  25. 25

    Revelo, N. H. et al. A new probe for super-resolution imaging of membranes elucidates trafficking pathways. J. Cell Biol. 205, 591–606 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Walter, A. M. et al. The SNARE protein VTI1a functions in dense-core vesicle biogenesis. EMBO J. 33, 1681–1697 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Ramirez, D. M., Khvotchev, M., Trauterman, B. & Kavalali, E. T. VTI1a identifies a vesicle pool that preferentially recycles at rest and maintains spontaneous neurotransmission. Neuron 73, 121–134 (2012). This study identifies VTI1A as a selective marker for a population of spontaneously recycling synaptic vesicles using dual-colour fluorescence imaging. Using electrophysiology, it also shows that, in its native form, VTI1A selectively maintains spontaneous neurotransmitter release.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Hua, Z. et al. v-SNARE composition distinguishes synaptic vesicle pools. Neuron 71, 474–487 (2011). This paper reports that the vesicular SNARE protein VAMP7 tags a pool of vesicles that is distinct in its molecular composition and functional properties.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Ramirez, D. M. & Kavalali, E. T. The role of non-canonical SNAREs in synaptic vesicle recycling. Cell. Logist. 2, 20–27 (2012).

    PubMed  PubMed Central  Google Scholar 

  30. 30

    Antonin, W., Riedel, D. & von Mollard, G. F. The SNARE Vti1a-ß is localized to small synaptic vesicles and participates in a novel SNARE complex. J. Neurosci. 20, 5724–5732 (2000).

    CAS  PubMed  Google Scholar 

  31. 31

    Scheuber, A. et al. Loss of AP-3 function affects spontaneous and evoked release at hippocampal mossy fiber synapses. Proc. Natl Acad. Sci. USA 103, 16562–16567 (2006).

    CAS  PubMed  Google Scholar 

  32. 32

    Muzerelle, A. et al. Tetanus neurotoxin-insensitive vesicle-associated membrane protein localizes to a presynaptic membrane compartment in selected terminal subsets of the rat brain. Neuroscience 122, 59–75 (2003).

    CAS  PubMed  Google Scholar 

  33. 33

    Bal, M. et al. Reelin mobilizes a VAMP7-dependent synaptic vesicle pool and selectively augments spontaneous neurotransmission. Neuron 80, 934–946 (2013). This study demonstrates that VAMP7-enriched vesicles could be swiftly and selectively mobilized by the small increases in presynaptic Ca2+ concentration that occur in response to neuromodulators, such as the secreted glycoprotein reelin.

    CAS  PubMed  Google Scholar 

  34. 34

    Raingo, J. et al. VAMP4 directs synaptic vesicles to a pool that selectively maintains asynchronous neurotransmission. Nature Neurosci. 15, 738–745 (2012).

    CAS  PubMed  Google Scholar 

  35. 35

    Mehta, B., Snellman, J., Chen, S., Li, W. & Zenisek, D. Synaptic ribbons influence the size and frequency of miniature-like evoked postsynaptic currents. Neuron 77, 516–527 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Zhou, K., Stawicki, T. M., Goncharov, A. & Jin, Y. Position of UNC-13 in the active zone regulates synaptic vesicle release probability and release kinetics. eLife 2, e01180 (2013).

    PubMed  PubMed Central  Google Scholar 

  37. 37

    Deak, F., Shin, O. H., Kavalali, E. T. & Sudhof, T. C. Structural determinants of synaptobrevin 2 function in synaptic vesicle fusion. J. Neurosci. 26, 6668–6676 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Weber, J. P., Reim, K. & Sorensen, J. B. Opposing functions of two sub-domains of the SNARE-complex in neurotransmission. EMBO J. 29, 2477–2490 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Zhou, P. et al. Syntaxin-1 N-peptide and Habc-domain perform distinct essential functions in synaptic vesicle fusion. EMBO J. 32, 159–171 (2013).

    CAS  PubMed  Google Scholar 

  40. 40

    Maximov, A. & Sudhof, T. C. Autonomous function of synaptotagmin 1 in triggering synchronous release independent of asynchronous release. Neuron 48, 547–554 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Liu, H., Dean, C., Arthur, C. P., Dong, M. & Chapman, E. R. Autapses and networks of hippocampal neurons exhibit distinct synaptic transmission phenotypes in the absence of synaptotagmin I. J. Neurosci. 29, 7395–7403 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Wierda, K. D. & Sorensen, J. B. Innervation by a GABAergic neuron depresses spontaneous release in glutamatergic neurons and unveils the clamping phenotype of synaptotagmin-1. J. Neurosci. 34, 2100–2110 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Geppert, M. et al. Synaptotagmin I: a major Ca2+ sensor for transmitter release at a central synapse. Cell 79, 717–727 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Riedel, D. et al. Rab3D is not required for exocrine exocytosis but for maintenance of normally sized secretory granules. Mol. Cell. Biol. 22, 6487–6497 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Kerr, A. M., Reisinger, E. & Jonas, P. Differential dependence of phasic transmitter release on synaptotagmin 1 at GABAergic and glutamatergic hippocampal synapses. Proc. Natl Acad. Sci. USA 105, 15581–15586 (2008).

    CAS  PubMed  Google Scholar 

  46. 46

    Xu, J., Pang, Z. P., Shin, O. H. & Sudhof, T. C. Synaptotagmin-1 functions as a Ca2+ sensor for spontaneous release. Nature Neurosci. 12, 759–766 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Huntwork, S. & Littleton, J. T. A complexin fusion clamp regulates spontaneous neurotransmitter release and synaptic growth. Nature Neurosci. 10, 1235–1237 (2007).

    CAS  PubMed  Google Scholar 

  48. 48

    Yang, X., Cao, P. & Sudhof, T. C. Deconstructing complexin function in activating and clamping Ca2+-triggered exocytosis by comparing knockout and knockdown phenotypes. Proc. Natl Acad. Sci. USA 110, 20777–20782 (2013).

    CAS  PubMed  Google Scholar 

  49. 49

    Groffen, A. J. et al. Doc2b is a high-affinity Ca2+ sensor for spontaneous neurotransmitter release. Science 327, 1614–1618 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Pang, Z. P. et al. Doc2 supports spontaneous synaptic transmission by a Ca2+-independent mechanism. Neuron 70, 244–251 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Yao, J., Gaffaney, J. D., Kwon, S. E. & Chapman, E. R. Doc2 is a Ca2+ sensor required for asynchronous neurotransmitter release. Cell 147, 666–677 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Wang, D. et al. Ca2+–calmodulin regulates SNARE assembly and spontaneous neurotransmitter release via v-ATPase subunit V0a1. J. Cell Biol. 205, 21–31 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Nosyreva, E. et al. Acute suppression of spontaneous neurotransmission drives synaptic potentiation. J. Neurosci. 33, 6990–7002 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Ertunc, M. et al. Fast synaptic vesicle reuse slows the rate of synaptic depression in the CA1 region of hippocampus. J. Neurosci. 27, 341–354 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Sara, Y., Virmani, T., Deak, F., Liu, X. & Kavalali, E. T. An isolated pool of vesicles recycles at rest and drives spontaneous neurotransmission. Neuron 45, 563–573 (2005). Using a combination of FM dye-based imaging of synaptic vesicle trafficking and electrophysiology, this study shows that the vesicle pools underlying spontaneous and evoked release are different and recycle independently.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Groemer, T. W. & Klingauf, J. Synaptic vesicles recycling spontaneously and during activity belong to the same vesicle pool. Nature Neurosci. 10, 145–147 (2007).

    CAS  PubMed  Google Scholar 

  57. 57

    Hua, Y., Sinha, R., Martineau, M., Kahms, M. & Klingauf, J. A common origin of synaptic vesicles undergoing evoked and spontaneous fusion. Nature Neurosci. 13, 1451–1453 (2010).

    CAS  PubMed  Google Scholar 

  58. 58

    Wilhelm, B. G., Groemer, T. W. & Rizzoli, S. O. The same synaptic vesicles drive active and spontaneous release. Nature Neurosci. 13, 1454–1456 (2010).

    CAS  PubMed  Google Scholar 

  59. 59

    Chung, C., Barylko, B., Leitz, J., Liu, X. & Kavalali, E. T. Acute dynamin inhibition dissects synaptic vesicle recycling pathways that drive spontaneous and evoked neurotransmission. J. Neurosci. 30, 1363–1376 (2010). This paper suggests that both synchronous- and asynchronous-evoked release originate from a pool of vesicles that recycles rapidly in a dynamin-dependent manner, whereas vesicles released spontaneously are derived from a separate pool that does not require dynamin for recycling.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Raimondi, A. et al. Overlapping role of dynamin isoforms in synaptic vesicle endocytosis. Neuron 70, 1100–1114 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Koenig, J. H. & Ikeda, K. Contribution of active zone subpopulation of vesicles to evoked and spontaneous release. J. Neurophysiol. 81, 1495–1505 (1999).

    CAS  PubMed  Google Scholar 

  62. 62

    Kavalali, E. T. & Jorgensen, E. M. Visualizing presynaptic function. Nature Neurosci. 17, 10–16 (2014).

    CAS  PubMed  Google Scholar 

  63. 63

    Fredj, N. B. & Burrone, J. A resting pool of vesicles is responsible for spontaneous vesicle fusion at the synapse. Nature Neurosci. 12, 751–758 (2009). This paper uses a novel imaging technique that exploits the high-affinity avidin–biotin interaction to detect spontaneous and activity-dependent synaptic vesicle recycling and provides evidence for their segregation.

    PubMed  Google Scholar 

  64. 64

    Peng, A., Rotman, Z., Deng, P. Y. & Klyachko, V. A. Differential motion dynamics of synaptic vesicles undergoing spontaneous and activity-evoked endocytosis. Neuron 73, 1108–1115 (2012).

    CAS  PubMed  Google Scholar 

  65. 65

    Atasoy, D. et al. Spontaneous and evoked glutamate release activates two populations of NMDA receptors with limited overlap. J. Neurosci. 28, 10151–10166 (2008). This study takes advantage of the use-dependent NMDA receptor antagonist MK-801 and uses electrophysiology to demonstrate that glutamate released spontaneously or as a result of action potential stimulation activates different populations of NMDA receptors. These observations are supported by imaging of both spontaneous and evoked vesicle fusion in single synaptic boutons and by modelling studies that are consistent with two separate receptor populations.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Sara, Y., Bal, M., Adachi, M., Monteggia, L. M. & Kavalali, E. T. Use-dependent AMPA receptor block reveals segregation of spontaneous and evoked glutamatergic neurotransmission. J. Neurosci. 31, 5378–5382 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Lu, H. E., MacGillavry, H. D., Frost, N. A. & Blanpied, T. A. Multiple spatial and kinetic subpopulations of CaMKII in spines and dendrites as resolved by single-molecule tracking PALM. J. Neurosci. 34, 7600–7610 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    MacGillavry, H. D., Song, Y., Raghavachari, S. & Blanpied, T. A. Nanoscale scaffolding domains within the postsynaptic density concentrate synaptic AMPA receptors. Neuron 78, 615–622 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Zenisek, D. Vesicle association and exocytosis at ribbon and extraribbon sites in retinal bipolar cell presynaptic terminals. Proc. Natl Acad. Sci. USA 105, 4922–4927 (2008). This paper provides evidence for the spatial segregation of different types of neurotransmission using single-vesicle imaging of goldfish bipolar cell ribbon synapses. Vesicles released as a result of stimulation are predominantly localized to the ribbon, whereas spontaneous release often occurs at extra-ribbon sites.

    CAS  PubMed  Google Scholar 

  70. 70

    Melom, J. E., Akbergenova, Y., Gavornik, J. P. & Littleton, J. T. Spontaneous and evoked release are independently regulated at individual active zones. J. Neurosci. 33, 17253–17263 (2013). This study uses transgenic expression of GCAMP5 at the D. melanogaster neuromuscular junction and detected unitary spontaneous and action potential-evoked postsynaptic Ca2+ transients. In most synaptic spots, coexistence of spontaneous and evoked signals was observed. However, approximately 22% of all synaptic regions selectively participated in spontaneous neurotransmission. Importantly, in the synaptic boutons that maintain both evoked and spontaneous neurotransmission, there was no significant correlation between the propensities of the two forms of neurotransmitter release.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Peled, E. S., Newman, Z. L. & Isacoff, E. Y. Evoked and spontaneous transmission favored by distinct sets of synapses. Curr. Biol. 24, 484–493 (2014). This study uses a similar strategy as that used in reference 70 and demonstrates substantial separation among the loci for evoked and spontaneous neurotransmission. However, it reports an inverse correlation between the propensities of evoked and spontaneous fusion events.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Walter, A. M., Haucke, V. & Sigrist, S. J. Neurotransmission: spontaneous and evoked release filing for divorce. Curr. Biol. 24, R192–R194 (2014).

    CAS  PubMed  Google Scholar 

  73. 73

    Polo-Parada, L., Bose, C. M. & Landmesser, L. T. Alterations in transmission, vesicle dynamics, and transmitter release machinery at NCAM-deficient neuromuscular junctions. Neuron 32, 815–828 (2001).

    CAS  PubMed  Google Scholar 

  74. 74

    Glitsch, M. Selective inhibition of spontaneous but not Ca2+-dependent release machinery by presynaptic group II mGluRs in rat cerebellar slices. J. Neurophysiol. 96, 86–96 (2006).

    CAS  PubMed  Google Scholar 

  75. 75

    Pan, Z. H., Segal, M. M. & Lipton, S. A. Nitric oxide-related species inhibit evoked neurotransmission but enhance spontaneous miniature synaptic currents in central neuronal cultures. Proc. Natl Acad. Sci. USA 93, 15423–15428 (1996).

    CAS  PubMed  Google Scholar 

  76. 76

    Penzo, M. A. & Pena, J. L. Depolarization-induced suppression of spontaneous release in the avian midbrain. J. Neurosci. 31, 3602–3609 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    McArdle, J. J., Sellin, L. C., Coakley, K. M., Potian, J. G. & Hognason, K. Mefloquine selectively increases asynchronous acetylcholine release from motor nerve terminals. Neuropharmacology 50, 345–353 (2006).

    CAS  PubMed  Google Scholar 

  78. 78

    Nelson, E. D., Kavalali, E. T. & Monteggia, L. M. Activity-dependent suppression of miniature neurotransmission through the regulation of DNA methylation. J. Neurosci. 28, 395–406 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Nelson, E. D., Kavalali, E. T. & Monteggia, L. M. MeCP2-dependent transcriptional repression regulates excitatory neurotransmission. Curr. Biol. 16, 710–716 (2006).

    CAS  PubMed  Google Scholar 

  80. 80

    Zamir, O. & Charlton, M. P. Cholesterol and synaptic transmitter release at crayfish neuromuscular junctions. J. Physiol. 571, 83–99 (2006).

    CAS  PubMed  Google Scholar 

  81. 81

    Wasser, C. R., Ertunc, M., Liu, X. & Kavalali, E. T. Cholesterol-dependent balance between evoked and spontaneous synaptic vesicle recycling. J. Physiol. 579, 413–429 (2007).

    CAS  PubMed  Google Scholar 

  82. 82

    Pratt, K. G., Zhu, P., Watari, H., Cook, D. G. & Sullivan, J. M. A novel role for γ-secretase: selective regulation of spontaneous neurotransmitter release from hippocampal neurons. J. Neurosci. 31, 899–906 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Peters, J. H., McDougall, S. J., Fawley, J. A., Smith, S. M. & Andresen, M. C. Primary afferent activation of thermosensitive TRPV1 triggers asynchronous glutamate release at central neurons. Neuron 65, 657–669 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Fawley, J. A., Hofmann, M. E. & Andresen, M. C. Cannabinoid 1 and transient receptor potential vanilloid 1 receptors discretely modulate evoked glutamate separately from spontaneous glutamate transmission. J. Neurosci. 34, 8324–8332 (2014).

    PubMed  PubMed Central  Google Scholar 

  85. 85

    Williams, C. et al. Coactivation of multiple tightly coupled calcium channels triggers spontaneous release of GABA. Nature Neurosci. 15, 1195–1197 (2012).

    CAS  PubMed  Google Scholar 

  86. 86

    Goswami, S. P., Bucurenciu, I. & Jonas, P. Miniature IPSCs in hippocampal granule cells are triggered by voltage-gated Ca2+ channels via microdomain coupling. J. Neurosci. 32, 14294–14304 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Ermolyuk, Y. S. et al. Differential triggering of spontaneous glutamate release by P/Q-, N- and R-type Ca2+ channels. Nature Neurosci. 16, 1754–1763 (2013).

    CAS  PubMed  Google Scholar 

  88. 88

    Vyleta, N. P. & Smith, S. M. Spontaneous glutamate release is independent of calcium influx and tonically activated by the calcium-sensing receptor. J. Neurosci. 31, 4593–4606 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Kochubey, O. & Schneggenburger, R. Synaptotagmin increases the dynamic range of synapses by driving Ca2+-evoked release and by clamping a near-linear remaining Ca2+ sensor. Neuron 69, 736–748 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Chicka, M. C., Hui, E., Liu, H. & Chapman, E. R. Synaptotagmin arrests the SNARE complex before triggering fast, efficient membrane fusion in response to Ca2+. Nature Struct. Mol. Biol. 15, 827–835 (2008).

    CAS  Google Scholar 

  91. 91

    Murthy, V. N. & Stevens, C. F. Reversal of synaptic vesicle docking at central synapses. Nature Neurosci. 2, 503–507 (1999).

    CAS  PubMed  Google Scholar 

  92. 92

    Carter, A. G. & Regehr, W. G. Quantal events shape cerebellar interneuron firing. Nature Neurosci. 5, 1309–1318 (2002).

    CAS  PubMed  Google Scholar 

  93. 93

    Sutton, M. A., Taylor, A. M., Ito, H. T., Pham, A. & Schuman, E. M. Postsynaptic decoding of neural activity: eEF2 as a biochemical sensor coupling miniature synaptic transmission to local protein synthesis. Neuron 55, 648–661 (2007). This paper identifies the enzyme eEF2 kinase, which is involved in regulation of ribosomal translocation, as the link between mEPSCs and dendritic protein synthesis, and presents strong evidence for differential signalling pathways that function downstream of spontaneous and action potential-evoked transmission.

    CAS  PubMed  Google Scholar 

  94. 94

    Sutton, M. A. et al. Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis. Cell 125, 785–799 (2006). This study shows that miniature release events bidirectionally control dendritic protein synthesis by describing a specific role for spontaneous transmission in homeostatic plasticity.

    CAS  Google Scholar 

  95. 95

    Espinosa, F. & Kavalali, E. T. NMDA receptor activation by spontaneous glutamatergic neurotransmission. J. Neurophysiol. 101, 2290–2296 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Autry, A. E. et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475, 91–95 (2011). This study shows that the rapid antidepressant action of the NMDA receptor blocker ketamine in vivo occurs owing to blockade of spontaneous NMDA receptor-driven synaptic events, which lead to deactivation of eEF2 kinase, reduced eEF2 phosphorylation and increased levels of BDNF.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Gideons, E. S., Kavalali, E. T. & Monteggia, L. M. Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses. Proc. Natl Acad. Sci. USA 111, 8649–8654 (2014).

    CAS  PubMed  Google Scholar 

  98. 98

    Jahr, C. E. & Stevens, C. F. Voltage dependence of NMDA-activated macroscopic conductances predicted by single-channel kinetics. J. Neurosci. 10, 3178–3182 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Aoto, J., Nam, C. I., Poon, M. M., Ting, P. & Chen, L. Synaptic signaling by all-trans retinoic acid in homeostatic synaptic plasticity. Neuron 60, 308–320 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Wang, H. L., Zhang, Z., Hintze, M. & Chen, L. Decrease in calcium concentration triggers neuronal retinoic acid synthesis during homeostatic synaptic plasticity. J. Neurosci. 31, 17764–17771 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Lalonde, J., Saia, G. & Gill, G. Store-operated calcium entry promotes the degradation of the transcription factor Sp4 in resting neurons. Sci. Signal. 7, ra51 (2014).

    PubMed  PubMed Central  Google Scholar 

  102. 102

    Lindskog, M. et al. Postsynaptic GluA1 enables acute retrograde enhancement of presynaptic function to coordinate adaptation to synaptic inactivity. Proc. Natl Acad. Sci. USA 107, 21806–21811 (2010).

    CAS  PubMed  Google Scholar 

  103. 103

    Jakawich, S. K. et al. Local presynaptic activity gates homeostatic changes in presynaptic function driven by dendritic BDNF synthesis. Neuron 68, 1143–1158 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Mozhayeva, M. G., Sara, Y., Liu, X. & Kavalali, E. T. Development of vesicle pools during maturation of hippocampal synapses. J. Neurosci. 22, 654–665 (2002).

    CAS  PubMed  Google Scholar 

  105. 105

    Andreae, L. C., Fredj, N. B. & Burrone, J. Independent vesicle pools underlie different modes of release during neuronal development. J. Neurosci. 32, 1867–1874 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Hsia, A. Y., Malenka, R. C. & Nicoll, R. A. Development of excitatory circuitry in the hippocampus. J. Neurophysiol. 79, 2013–2024 (1998).

    CAS  Google Scholar 

  107. 107

    McKinney, R. A., Capogna, M., Durr, R., Gahwiler, B. H. & Thompson, S. M. Miniature synaptic events maintain dendritic spines via AMPA receptor activation. Nature Neurosci. 2, 44–49 (1999).

    CAS  PubMed  Google Scholar 

  108. 108

    McAllister, A. K., Katz, L. C. & Lo, D. C. Neurotrophin regulation of cortical dendritic growth requires activity. Neuron 17, 1057–1064 (1996).

    CAS  PubMed  Google Scholar 

  109. 109

    Choi, B. J. et al. Miniature neurotransmission regulates Drosophila synaptic structural maturation. Neuron 82, 618–634 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Sutton, M. A. & Schuman, E. M. Dendritic protein synthesis, synaptic plasticity, and memory. Cell 127, 49–58 (2006).

    CAS  PubMed  Google Scholar 

  111. 111

    Frank, C. A., Kennedy, M. J., Goold, C. P., Marek, K. W. & Davis, G. W. Mechanisms underlying the rapid induction and sustained expression of synaptic homeostasis. Neuron 52, 663–677 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Kavalali, E. T. & Monteggia, L. M. Synaptic mechanisms underlying rapid antidepressant action of ketamine. Am. J. Psychiatry 169, 1150–1156 (2012).

    PubMed  Google Scholar 

  113. 113

    Hawkins, R. D. Possible contributions of a novel form of synaptic plasticity in Aplysia to reward, memory, and their dysfunctions in mammalian brain. Learn. Memory 20, 580–591 (2013).

    CAS  Google Scholar 

  114. 114

    Jin, I. et al. Spontaneous transmitter release recruits postsynaptic mechanisms of long-term and intermediate-term facilitation in Aplysia. Proc. Natl Acad. Sci. USA 109, 9137–9142 (2012).

    CAS  PubMed  Google Scholar 

  115. 115

    Jin, I. et al. Spontaneous transmitter release is critical for the induction of long-term and intermediate-term facilitation in Aplysia. Proc. Natl Acad. Sci. USA 109, 9131–9136 (2012).

    CAS  PubMed  Google Scholar 

  116. 116

    Trigo, F. F. et al. Presynaptic miniature GABAergic currents in developing interneurons. Neuron 66, 235–247 (2010).

    CAS  PubMed  Google Scholar 

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Correspondence to Ege T. Kavalali.

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Docked vesicles

Synaptic vesicles that are tethered to the presynaptic membrane or the active zone structure. According to current views, not all docked vesicles are fully primed for fusion and release of neurotransmitter.

Primed vesicles

Vesicles that are docked and that have advanced through all the necessary molecular rearrangements of the SNARE (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor) fusion machinery; that is, vesicles waiting for the influx of Ca2+ ions to trigger fusion. According to the current view, vesicle priming requires partial or full assembly of the SNARE complex, as well as interaction of SNAREs with other key fusion proteins, such as MUNC18, MUNC13 and other components of the presynaptic active zone.

Super-resolution microscopy

A form of light microscopy that achieves a spatial resolution of 50–100 nm, which is beyond the limit set by diffraction; it includes stimulated emission depletion microscopy (STED), photoactivated localization microscopy (PALM) and stochastic optical reconstruction microscopy (STORM).

Total internal reflection fluorescence microscopy

A high-resolution fluorescence microscopy technique that takes advantage of a laser-induced evanescent wave of fluorescence emission which is very close to the interface of two media that have different refractive indices.

Ribbon synapses

Synapses characterized by an electron-dense ribbon or bar in the presynaptic terminal. The ribbon is commonly oriented at a right angle to the membrane and sits just above an evaginated ridge. It is thought that the ribbons help to guide vesicles to the release sites. Ribbon synapses are commonly found in the retina and cochlea of vertebrates.

Synaptic scaling

Upscaling or downscaling of the quantal amplitude of all synapses onto a postsynaptic neuron in response to long-lasting changes in neuronal activity.

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Kavalali, E. The mechanisms and functions of spontaneous neurotransmitter release. Nat Rev Neurosci 16, 5–16 (2015).

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