Synaptic plasticity at hippocampal mossy fibre synapses

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Abstract
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.