Determinants of Synapse Diversity Revealed by Super-resolution Quantal Transmission and Active Zone Imaging

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Jan 12

PMID 35017509

Authors

Zachary L Newman

Dariya Bakshinskaya

Ryan Schultz

Samuel J Kenny

Seonah Moon

Krisha Aghi

Cherise Stanley

Nadia Marnani

Rachel Li

Julia Bleier

Ke Xu

Ehud Y Isacoff

Affiliations

Soon will be listed here.

Abstract

Neural circuit function depends on the pattern of synaptic connections between neurons and the strength of those connections. Synaptic strength is determined by both postsynaptic sensitivity to neurotransmitter and the presynaptic probability of action potential evoked transmitter release (P). Whereas morphology and neurotransmitter receptor number indicate postsynaptic sensitivity, presynaptic indicators and the mechanism that sets P remain to be defined. To address this, we developed QuaSOR, a super-resolution method for determining P from quantal synaptic transmission imaging at hundreds of glutamatergic synapses at a time. We mapped the P onto super-resolution 3D molecular reconstructions of the presynaptic active zones (AZs) of the same synapses at the Drosophila larval neuromuscular junction (NMJ). We find that P varies greatly between synapses made by a single axon, quantify the contribution of key AZ proteins to P diversity and find that one of these, Complexin, suppresses spontaneous and evoked transmission differentially, thereby generating a spatial and quantitative mismatch between release modes. Transmission is thus regulated by the balance and nanoscale distribution of release-enhancing and suppressing presynaptic proteins to generate high signal-to-noise evoked transmission.

Citing Articles

The Role of Complexity Theory in Understanding Brain's Neuron-Glia Interactions.

Di Chiano M, Milior P, Poulot-Becq-Giraudon Y, Lanfredini R, Milior G Eur J Neurosci. 2025; 61(5):e70050.

PMID: 40074717 PMC: 11903385. DOI: 10.1111/ejn.70050.

Active zone maturation state controls synaptic output and release mode and is differentially regulated by neuronal activity.

Akbergenova Y, Matthias J, Littleton J bioRxiv. 2025; .

PMID: 39975213 PMC: 11838553. DOI: 10.1101/2025.02.03.636302.

Distinct input-specific mechanisms enable presynaptic homeostatic plasticity.

Chien C, He K, Perry S, Tchitchkan E, Han Y, Li X Sci Adv. 2025; 11(7):eadr0262.

PMID: 39951523 PMC: 11827636. DOI: 10.1126/sciadv.adr0262.

Specific presynaptic functions require distinct Ca2 splice isoforms.

Bell C, Kilo L, Gottschalk D, Arian J, Deneke L, Kern H Elife. 2025; 13.

PMID: 39951027 PMC: 11828482. DOI: 10.7554/eLife.100394.

Synapse-specific catecholaminergic modulation of neuronal glutamate release.

Bakshinska D, Liu W, Schultz R, Stowers R, Hoagland A, Cypranowska C Proc Natl Acad Sci U S A. 2025; 122(1):e2420496121.

PMID: 39793084 PMC: 11725921. DOI: 10.1073/pnas.2420496121.

References

Schaub J, Lu X, Doneske B, Shin Y, McNew J . Hemifusion arrest by complexin is relieved by Ca2+-synaptotagmin I. Nat Struct Mol Biol. 2006; 13(8):748-50. DOI: 10.1038/nsmb1124. View

Buhl L, Jorquera R, Akbergenova Y, Huntwork-Rodriguez S, Volfson D, Littleton J . Differential regulation of evoked and spontaneous neurotransmitter release by C-terminal modifications of complexin. Mol Cell Neurosci. 2012; 52:161-72. PMC: 3540146. DOI: 10.1016/j.mcn.2012.11.009. View

Fekete A, Nakamura Y, Yang Y, Herlitze S, Mark M, DiGregorio D . Underpinning heterogeneity in synaptic transmission by presynaptic ensembles of distinct morphological modules. Nat Commun. 2019; 10(1):826. PMC: 6379440. DOI: 10.1038/s41467-019-08452-2. View

Ward B, McGuinness L, Akerman C, Fine A, Bliss T, Emptage N . State-dependent mechanisms of LTP expression revealed by optical quantal analysis. Neuron. 2006; 52(4):649-61. DOI: 10.1016/j.neuron.2006.10.007. View

Aberle H, Pejmun Haghighi A, Fetter R, McCabe B, Magalhaes T, Goodman C . wishful thinking encodes a BMP type II receptor that regulates synaptic growth in Drosophila. Neuron. 2002; 33(4):545-58. DOI: 10.1016/s0896-6273(02)00589-5. View

Nusser Z, Lujan R, Laube G, Roberts J, Molnar E, Somogyi P . Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus. Neuron. 1998; 21(3):545-59. DOI: 10.1016/s0896-6273(00)80565-6. View

Holderith N, Lorincz A, Katona G, Rozsa B, Kulik A, Watanabe M . Release probability of hippocampal glutamatergic terminals scales with the size of the active zone. Nat Neurosci. 2012; 15(7):988-97. PMC: 3386897. DOI: 10.1038/nn.3137. View

Melom J, Akbergenova Y, Gavornik J, Littleton J . Spontaneous and evoked release are independently regulated at individual active zones. J Neurosci. 2013; 33(44):17253-63. PMC: 3812501. DOI: 10.1523/JNEUROSCI.3334-13.2013. View

Dittman J, Ryan T . The control of release probability at nerve terminals. Nat Rev Neurosci. 2019; 20(3):177-186. DOI: 10.1038/s41583-018-0111-3. View

10.

Matz J, Gilyan A, Kolar A, McCarvill T, Krueger S . Rapid structural alterations of the active zone lead to sustained changes in neurotransmitter release. Proc Natl Acad Sci U S A. 2010; 107(19):8836-41. PMC: 2889309. DOI: 10.1073/pnas.0906087107. View

11.

Peled E, Newman Z, Isacoff E . Evoked and spontaneous transmission favored by distinct sets of synapses. Curr Biol. 2014; 24(5):484-93. PMC: 4017949. DOI: 10.1016/j.cub.2014.01.022. View

12.

Bossi M, Folling J, Belov V, Boyarskiy V, Medda R, Egner A . Multicolor far-field fluorescence nanoscopy through isolated detection of distinct molecular species. Nano Lett. 2008; 8(8):2463-8. DOI: 10.1021/nl801471d. View

13.

Branco T, Marra V, Staras K . Examining size-strength relationships at hippocampal synapses using an ultrastructural measurement of synaptic release probability. J Struct Biol. 2009; 172(2):203-10. PMC: 3084449. DOI: 10.1016/j.jsb.2009.10.014. View

14.

Oertner T, Sabatini B, Nimchinsky E, Svoboda K . Facilitation at single synapses probed with optical quantal analysis. Nat Neurosci. 2002; 5(7):657-64. DOI: 10.1038/nn867. View

15.

Reid C, Dixon D, Takahashi M, Bliss T, Fine A . Optical quantal analysis indicates that long-term potentiation at single hippocampal mossy fiber synapses is expressed through increased release probability, recruitment of new release sites, and activation of silent synapses. J Neurosci. 2004; 24(14):3618-26. PMC: 6729736. DOI: 10.1523/JNEUROSCI.3567-03.2004. View

16.

Preibisch S, Saalfeld S, Tomancak P . Globally optimal stitching of tiled 3D microscopic image acquisitions. Bioinformatics. 2009; 25(11):1463-5. PMC: 2682522. DOI: 10.1093/bioinformatics/btp184. View

17.

Brunger A, Choi U, Lai Y, Leitz J, Zhou Q . Molecular Mechanisms of Fast Neurotransmitter Release. Annu Rev Biophys. 2018; 47:469-497. PMC: 6378885. DOI: 10.1146/annurev-biophys-070816-034117. View

18.

Bruckner J, Zhan H, Gratz S, Rao M, Ukken F, Zilberg G . Fife organizes synaptic vesicles and calcium channels for high-probability neurotransmitter release. J Cell Biol. 2016; 216(1):231-246. PMC: 5223599. DOI: 10.1083/jcb.201601098. View

19.

Wagh D, Rasse T, Asan E, Hofbauer A, Schwenkert I, Durrbeck H . Bruchpilot, a protein with homology to ELKS/CAST, is required for structural integrity and function of synaptic active zones in Drosophila. Neuron. 2006; 49(6):833-44. DOI: 10.1016/j.neuron.2006.02.008. View

20.

Karunanithi S, Lin Y, Odierna G, Menon H, Gonzalez J, Neely G . Activity-Dependent Global Downscaling of Evoked Neurotransmitter Release across Glutamatergic Inputs in . J Neurosci. 2020; 40(42):8025-8041. PMC: 7574657. DOI: 10.1523/JNEUROSCI.0349-20.2020. View