Section III
Long-term potentiation of synaptic transmission at the mossy fiber–granule cell relay of cerebellum

https://doi.org/10.1016/S0079-6123(04)48007-8Get rights and content

Abstract

In the last decade, the physiology of cerebellar neurons and synapses has been extended to a considerable extent. We have found that the mossy fiber–granule cell relay can generate a complex form of long-term potentiation (mf–GrC LTP) following high-frequency mf discharge.

Induction. Mf–GrC LTP depends on NMDA and mGlu receptor activation, intracellular Ca2+ increase, PKC activation, and NO production. The preventative action of intracellular agents (BAPTA, PKC-inhibitors) and of membrane hyperpolarization, and the correlated increase in intracellular Ca2+ observed using florescent dyes, indicate that induction occurs postsynaptically.

Expression. Expression includes three components: (a) an increase of synaptic currents, (b) an increase of intrinsic excitability in GrC, and (c) an increase of intrinsic excitability in mf terminals. Based on quantal analysis, the EPSC increase is mostly explained by enhanced neurotransmitter release. NO is a candidate retrograde neurotransmitter which could determine both presynaptic current changes and LTP. NO cascade blockers inhibit both presynaptic current changes and LTP. The increase in intrinsic excitability involves a raise in apparent input resistance in the subthreshold region and a spike threshold reduction.

Together with other forms of cerebellar plasticity, mf–GrC LTP opens new hypothesis on how the cerebellum processes incoming information.

Section snippets

The cerebellum and the mossy fiber–granule cell relay

The cerebellum is a brain structure of primary importance for the coordination of movement, and is also probably involved in processing higher brain functions (Ghez and Thach, 2003). The basic architecture of the cerebellar circuitry is well known (Eccles et al., 1967; Ito, 1984). The cerebellum receives two main inputs through mossy fibers (mfs) and climbing fibers (cfs). Cfs originate in the inferior olivary nucleus and innervate Purkinje cells (PCs). Mfs are the largest cerebellar afferent

Mossy fiber–granule cell long-term potentiation (LTP)

Marr (1969) explicitly negated the possibility that mf–GrC synaptic weights could be modified by activity. He noted that ‘sooner or later all weights would be saturated ’ so that plasticity would not be useful. Thus, Marr’s model did not include any mf–GrC synaptic plasticity, although the subsequent extension due to Albus (1971) was more permissive. However, the observation that mf discharge consists of high-frequency bursts (Kase et al., 1980) and that GrCs express NMDA receptors, which

Functional consequences of mossy fiber–granule cell LTP

The cerebellum is thought to operate in feed-forward mode anticipating the corrections needed to regulate complex sequences of movements (Ghez and Thach, 2003). As every feed-forward device, the cerebellum needs to store information to be used in a predictive manner. No surprise therefore that the cerebellar circuitry expresses mechanisms for learning and memory. As proposed by Marr (1969), a major form of plasticity occurs at the pf-PC synapse, allowing heterosynaptic depression when a motor

Conclusions

Although several aspects remain to be investigated, mf–GrC LTP provides a wide substrate for information storage in the cerebellum. In the rat cerebellum, there are 1011 GrCs and four times as many mf–GrC synapses. Mathematical models have suggested that mf–GrC LTP improves mutual information transfer and regulates codon representation (Schweighofer et al., 2000; Philipona et al., 2003). Moreover, a preliminary investigation suggests a role in regulating neurotransmission dynamics (Nieus et

Acknowledgements

Supported by European Community grants IST-2001-35271 and QLG3-CT-2001-02256, by MIUR and INFM of Italy.

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