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Synaptic plasticity at hippocampal mossy fibre synapses

Key Points

  • The terminals of axons of dentate gyrus granule cells are known as 'mossy fibres'. Large mossy fibre boutons (MFBs) contact pyramidal cells in area CA3 of the hippocampus, whereas small terminals and filopodial extensions from MFBs target GABA (γ-aminobutyric acid)-containing interneurons.

  • Several properties distinguish the excitatory mossy fibre–pyramidal synapse from other synapses in the CNS, including low basal release probability, pronounced frequency facilitation and a lack of NMDA(N-methyl-D-aspartate) receptor (NMDAR) involvement in long-term potentiation (LTP).

  • Adenosine acting on presynaptic A1 adenosine receptors contributes to the low initial release probability at the mossy fibre–pyramidal cell synapse. Synaptically released glutamate can mediate negative and positive feedback by acting on presynaptic metabotropic glutamate receptors (mGluRs) and kainate receptors (KARs), respectively, depending on the frequency at which the synapse is activated.

  • Controversy surrounds the mechanism of LTP induction at the mossy fibre–pyramidal cell synapse, which does not depend on postsynaptic NMDAR activation. Whether postsynaptic Ca2+ influx has a role in mossy fibre LTP remains open to question, but there is strong evidence for an involvement of presynaptic Ca2+ channels. Presynaptic mGluRs and KARs might have a role in, but are not essential for, the induction of LTP at mossy fibre–pyramidal cell synapses.

  • The expression of mossy fibre LTP is presynaptic, due to an increase in transmitter release. Entry of Ca2+ into the presynaptic terminal is proposed to directly activate adenylyl cyclase AC1 and AC8, resulting in a rise in cyclic AMP that is necessary and sufficient for mossy fibre LTP.

  • Long-term depression (LTD) at mossy fibre–pyramidal cell synapses is thought to involve a reversal of the presynaptic processes that underlie LTP, although other forms of LTD might be expressed.

  • Mossy fibre–interneuron synapses show a range of short-term responses to repetitive stimulation, from pronounced depression to modest facilitation. Glutamate released at these synapses can activate Ca2+-permeable (CP) or Ca2+-impermeable (CI) postsynaptic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs).

  • Early studies failed to show LTP at mossy fibre–interneuron synapses, but more recent studies indicate that this form of plasticity can be induced. CP-AMPAR synapses show NMDAR-independent LTD, which seems to be expressed as a presynaptic decrease in neurotransmitter release, whereas CI-AMPAR synapses show robust, NMDAR-dependent LTD, expressed postsynaptically as a downregulation of AMPARs.

  • The study of hippocampal mossy fibre synapses has revealed a host of intriguing mechanisms by which synaptic strength can be controlled, and it seems likely that these synapses have only just begun to reveal their many secrets.

Abstract

The dentate gyrus provides the main input to the hippocampus. Information reaches the CA3 region through mossy fibre synapses made by dentate granule cell axons. Synaptic plasticity at the mossy fibre–pyramidal cell synapse is unusual for several reasons, including low basal release probability, pronounced frequency facilitation and a lack of N-methyl-D-aspartate receptor involvement in long-term potentiation. In the past few years, some of the mechanisms underlying the peculiar features of mossy fibre synapses have been elucidated. Here we describe recent work from several laboratories on the various forms of synaptic plasticity at hippocampal mossy fibre synapses. We conclude that these contacts have just begun to reveal their many secrets.

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Figure 1: Hippocampal mossy fibre synapses.
Figure 2: Modulation of synaptic efficacy by irregular spike trains.
Figure 3: Adenosine gates synaptic plasticity at hippocampal mossy fibre synapses.
Figure 4: Role of metabotropic glutamate receptors at hippocampal mossy fibre synapses.
Figure 5: Kainate receptors at hippocampal mossy fibre synapses.
Figure 6: Mossy fibre long-term potentiation and the role of α1E-containing Ca2+ channels.
Figure 7: Long-term depression at hippocampal mossy fibre synapses.
Figure 8: Target cell-specific mossy fibre synaptic plasticity.

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Acknowledgements

We thank A. Gundlfinger and J. Breustedt for critical reading of the manuscript and help with the figures. R.A.N. is a member of the Keck Centre for Integrative Neuroscience and the Silvio Conte Centre for Neuroscience Research and is supported by grants from the National Institutes of Health and Bristol-Myers Squibb. D.S. is supported by grants from the Deutsche Forschungsgemeinschaft (Emmy-Noether-Programm) and the Berlin Bernstein Centre for Computational Neuroscience.

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DATABASES

Entrez Gene

A1 adenosine receptor

AMPA receptors

Kainate receptors

mGluR receptors

NMDA receptors

FURTHER INFORMATION

Nicoll's homepage

Schmitz's homepage

Glossary

DENTATE HILUS

An area of the dentate gyrus beneath the granule cell layer that is rich in interneurons. The axons of granule cells pass through this area on the way to the CA3 region of the hippocampus.

STRATUM LUCIDUM

The layer in area CA3 of the hippocampus that harbours the axons and boutons of dentate gyrus granule cells.

PAIRED-PULSE FACILITATION

(PPF). A presynaptic form of short-term plasticity. PPF describes the ability of synapses to increase neurotransmitter release on the second of two closely spaced afferent stimulations and depends on the residual Ca2+ concentrations in the presynaptic terminal.

FREQUENCY FACILITATION

Another form of short-term plasticity, in which modest stimulus frequencies cause a growth in synaptic strength.

SYNAPTIC FAILURE

A failure occurs when a presynaptic action potential does not lead to a postsynaptic response.

ASSOCIATIONAL–COMMISSURAL SYNAPSE

Associational inputs are the projections from CA3 neurons to other CA3 cells on the same side of the brain. Commissural inputs are CA3–CA3 connections between the two hemispheres.

SCHAFFER COLLATERAL SYNAPSE

Contacts formed by axons of CA3 pyramidal cells of the hippocampus onto the dendrites of CA1 neurons.

METABOTROPIC GLUTAMATE RECEPTORS

Seven-transmembrane G-protein-coupled receptors that were discovered as a new type of glutamate receptor by their unique coupling mechanism and pharmacological characteristics. They can be expressed both pre- and postsynaptically.

KAINATE RECEPTORS

Ionotropic glutamate receptors that constitute a separate group from the NMDA (N-methyl-D-aspartate) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Five different kainate receptor subunits have been cloned.

PRESYNAPTIC FIBRE VOLLEY

The negative, extracellularly recorded wave that is detected when an action potential in a population of axons passes the recording electrode. The amplitude is proportional to the number of active presynaptic fibres, and so serves as an estimate of the strength of an afferent input.

COEFFICIENT OF VARIATION

(CV). A measure of variability — the mean response divided by the standard deviation of the response. The CV of evoked synaptic transmission (determined by repeatedly evoking release and calculating the mean and the standard deviation of the postsynaptic response) depends strongly on neurotransmitter release probability.

OUTSIDE-OUT PATCH

A variant of the patch-clamp technique, in which a patch of plasma membrane covers the tip of the electrode. The outside of the membrane is exposed to bathing solution.

TETANUS

A train of stimuli in which afferent axons are briefly activated at high frequency. In LTP experiments, a 1-s train of pulses delivered at a frequency of 100 Hz is commonly used to potentiate transmission. A 5-s train of 25 Hz is a particularly effective way to induce mossy fibre LTP.

PDZ DOMAIN

Many proteins contain one or more PDZ domains, which were named after the initial three members (PSD-95, Drosophila discs large protein, ZO-1). PDZ domains typically bind specific carboxy-terminal sequences in target proteins. Proteins that contain PDZ domains are thought to have a scaffolding role.

MINIATURE SYNAPTIC EVENTS

Postsynaptic potentials or currents observed in the absence of presynaptic action potentials; they are thought to correspond to the response elicited by a single vesicle of transmitter.

ACTIVE ZONE

A portion of the presynaptic membrane that faces the postsynaptic density across the synaptic cleft. It constitutes the site of synaptic vesicle clustering, docking and neurotransmitter release.

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Nicoll, R., Schmitz, D. Synaptic plasticity at hippocampal mossy fibre synapses. Nat Rev Neurosci 6, 863–876 (2005). https://doi.org/10.1038/nrn1786

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