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  • Review Article
  • Published:

Diversification of synaptic strength: presynaptic elements

Nature Reviews Neuroscience volume 3, pages 497–516 (2002)Cite this article

Key Points

  • Synapses are functionally diverse. For example, synaptic strength can differ markedly from one synapse to the next. How does this diversity arise? What are its underlying mechanisms? Both structural and molecular explanations have been put forward to account for synaptic differentiation.

  • It is possible to define two general cases of synaptic functional differentiation. In case I, different branches of the same neuron evoke synaptic responses of diverse character in various follower cells. It is thought that retrograde influences from the follower cells determine synaptic properties. In case II, different presynaptic neurons that supply the same follower cell evoke different postsynaptic responses. In this case, upstream determination of presynaptic properties seems to be more significant.

  • From a presynaptic perspective, how could synaptic structure modify synaptic strength? There are several possibilities. Specifically, there might be presynaptic differences in the number of active zones per synapse, the density of Ca2+ channels in the active zone, the size of synaptic vesicles, the spacing between vesicles and Ca2+ channels, and the number of readily releasable vesicles. There is evidence for the contribution of each of these factors to synaptic differentiation of both invertebrate and vertebrate synapses.

  • Although quantal size has been thought to depend largely on postsynaptic factors, several presynaptic factors might also affect this variable. They include variations in the size of vesicles, in the intravesicular transmitter concentration or in the properties of the fusion event. However, the contribution of differences in quantal size to synaptic diversity under normal circumstances is not fully understood.

  • The size of the readily releasable vesicle pool also contributes to differences in synaptic strength. There is a linear relationship between docked and readily releasable vesicles, and the readily releasable pool size is tightly linked to release probability and to synapse size. These relationships have been best established for synapses in culture; although they have been postulated to apply also to synapses in vivo, their validity remains to be tested.

  • The number of synaptic Ca2+ channels and the type of channel might also affect synaptic strength. However, evidence for such a link is, at best, suggestive, as crucial physiological experiments that show a causal relationship in situ are still lacking.

  • Differences in vesicle–channel spacing and intracellular Ca2+ buffers might also contribute to differences in synaptic strength. Their effects are also tightly linked to the structure of the active zone, which has been the subject of recent debate. There is evidence that, at some synapses, the disposition of the vesicles and the Ca2+ channels is quite regular. However, it is not clear that such an arrangement is found at other synapses, and there is some evidence that it is not.

  • Synaptic structural features cannot account fully for differences in synaptic strength. So, underlying molecular differences must make an important contribution. How well can the known molecular candidates explain synaptic differentiation? To participate in differentiation, the candidate molecules need to co-localize with the synaptic difference, their disturbance must affect synaptic differentiation, and there should be proof that they contribute to differentiation in vivo. Although there are many molecular candidates, the evidence for their contribution to normally occurring synaptic differentiation is so far incomplete.

  • Although we have started to link physiological properties with molecular and structural substrates, little progress has been made in matching these features. An important goal for future research will be to decipher more of the molecular and structural rules that govern the expression of physiological phenotypes. The structural approach has been the most successful so far, as it has produced some general principles of variations in synaptic strength. By contrast, closing the loop between molecular and physiological differentiation remains the greatest challenge for this field.

Abstract

Synapses are not static; their performance is modified adaptively in response to activity. Presynaptic mechanisms that affect the probability of transmitter release or the amount of transmitter that is released are important in synaptic diversification. Here, we address the diversity of presynaptic performance and its underlying mechanisms: how much of the variation can be accounted for by variation in synaptic morphology and how much by molecular differences? Significant progress has been made in defining presynaptic structural contributions to synaptic strength; by contrast, we know little about how presynaptic proteins produce normally observed functional differentiation, despite abundant information on presynaptic proteins and on the effects of their individual manipulation. Closing the gap between molecular and physiological synaptic diversification still represents a considerable challenge.

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Figure 1: Synaptic functional differentiation, case I: differences in the responses of a target cell to a single presynaptic neuron.
Figure 2: Synaptic functional differentiation, case II: responses evoked in a single target cell by different presynaptic inputs.
Figure 3: Presynaptic determinants of synaptic strength.
Figure 4: Quantal size and variance: evidence for presynaptic influence.
Figure 5: Synaptic vesicle pools and the putative contribution of readily releasable vesicles to synaptic strength.
Figure 6: Active zone structure.
Figure 7: Differential effects of Ca2+ buffers in mammalian central neurons.
Figure 8: Possible mechanisms that lead to differential synaptic strength.

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Acknowledgements

We thank M. Hegström-Wojtowicz for help in preparing the manuscript. L. Marin provided help with electron microscopy (presented in figure 4b); A. Miller, H. Bradacs and M. P. Charlton contributed to recent work on crustacean neuromuscular junctions. The authors' research is supported by the Natural Sciences and Engineering Research Council of Canada, and by the Canadian Institutes of Health Research. The authors dedicate this review to the memory of Professor C. K. Govind, University of Toronto, a significant contributor to crustacean synaptic biology, who died on 24 May 2002.

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Authors and Affiliations

  1. Department of Physiology, University of Toronto, Toronto, M5S 1A8, Ontario, Canada

    Harold L. Atwood & Shanker Karunanithi

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  1. Harold L. Atwood
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Correspondence to Harold L. Atwood.

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DATABASES

LocusLink

frequenin

KV1 channels

Munc 13

N-type Ca2+ channels

P/Q-type Ca2+ channels

R-type Ca2+ channels

SNAP-25

synaptobrevin

synaptotagmin

syntaxin

T-type Ca2+ channels

FURTHER INFORMATION

Encyclopedia of Life Sciences

calcium and neurotransmitter release

chemical synapses

long-term depression and depotentiation

long-term potentiation

synapses

synaptic plasticity: short term

synaptic vesicle traffic

Glossary

SYNAPTIC STRENGTH

The relative amplitude of the postsynaptic response that is generated by the activity of the presynaptic neuron.

ACTIVE ZONE

The site of the presynaptic terminal at which synaptic exocytosis occurs.

CLIMBING FIBRES

Cerebellar afferents that arise from the inferior olivary nucleus, each of which forms multiple synapses with a single Purkinje cell.

PARALLEL FIBRES

Axons of cerebellar granule cells. Parallel fibres emerge from the molecular layer of the cerebellar cortex towards the periphery, where they extend branches perpendicular to the main axis of the Purkinje neurons and form the so-called en passant synapses with this cell type.

QUANTAL SIZE

The mean amplitude of the postsynaptic response that results from the release of transmitter from a single synaptic vesicle.

HIPPOCAMPAL MOSSY FIBRES

Axons of granule cells, which form synapses with CA3 pyramidal neurons. Mossy fibre boutons are among the largest in the central nervous system.

READILY RELEASABLE VESICLES

Synaptic vesicles that are available for rapid fusion with the presynaptic membrane on arrival of a nerve impulse. They are docked to the membrane and have been biochemically primed for release.

VESICLE PRIMING

Primed vesicles are those that have acquired the biochemical attributes for fusion with the presynaptic membrane; they can release their transmitter on the arrival of a nerve impulse.

LONG-TERM POTENTIATION

A long-lasting increase in the efficacy of neurotransmission, which can be elicited by diverse patterns of synaptic activation.

QUANTAL VARIANCE

A measure of the variability of quantal events normalized to their mean amplitude. From the statistical point of view, quantal variance corresponds to the coefficient of variation of the responses — the standard deviation divided by the mean.

AMPEROMETRY

An electroanalytical technique that is based on the measurement of current flow through an electrochemical cell. In the case of exocytosis, the release of oxidizable substances (such as catecholamines) from single vesicles can be studied by amperometry using a carbon fibre electrode. The electrode is held at a voltage that causes the oxidation of the transmitter, and the resulting redox currents are measured with a patch-clamp amplifier.

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 transmitter.

SCHAFFER COLLATERALS

Axons of the CA3 pyramidal cells that form synapses with the apical dendrites of hippocampal CA1 neurons.

FREEZE FRACTURE

An electron-microscopic method in which rapidly frozen tissue is cracked to produce a fracture plane through the specimen. The surface of the fracture plane is shadowed by a heavy metal, and the specimen is digested away to leave a replica that can be examined under the electron microscope.

ATOMIC FORCE MICROSCOPY

A form of microscopy in which a probe is mechanically tracked over a surface of interest in a series of x–y scans. The force found at each coordinate is measured with piezoelectric sensors, providing information about the chemical nature of a surface.

ELECTRON MICROSCOPE TOMOGRAPHY

A method for the three-dimensional reconstruction of objects from a series of projection images that are recorded with a transmission electron microscope. It offers the opportunity to obtain spatial information on structural arrangements of cellular components.

PRESYNAPTIC GRID

A dense matrix of proteins that is associated with the active zone, which is thought to have a crucial role in defining the transmitter release sites.

MELANOTROPHS

Excitable cells from the pituitary that are specialized in secreting several peptide hormones such as β-endorphin and adrenocorticotropin.

SNARE PROTEINS

A family of membrane-tethered coiled-coil proteins that regulate exocytic reactions and target specificity in vesicular fusion processes. SNARE stands for 'soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor'.

CHROMAFFIN CELLS

Cells of the adrenal gland that store and secrete catecholamines. They are known as 'chromaffin' cells because of the ability of chromium salts to stain them.

CAGED MOLECULE

A labile derivative of a biologically active molecule that will break down after photolysis of the precursor to yield the bioactive compound.

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Atwood, H., Karunanithi, S. Diversification of synaptic strength: presynaptic elements. Nat Rev Neurosci 3, 497–516 (2002). https://doi.org/10.1038/nrn876

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